Heteroaromate OSC inhibitors

ABSTRACT

The present invention relates to heteroaromate OSC inhibitors. The compounds are useful for the treatment and/or prophylaxis of diseases which are associated with 2,3-oxidosqualene-lanosterol cyclase such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, gallstones, tumors and/or hyperproliferative disorders, and treatment and/or prophylaxis of impaired glucose tolerance and diabetes.

PRIORITY TO RELATED APPLICATIONS

This application is a Division of U.S. Ser. No. 11/178,164, filed Jul.8, 2005, now U.S. Pat. No. 7,173,043, issued Feb. 6, 2007, which is adivision of U.S. Ser. No. 09/999,424, filed Oct. 31, 2001, U.S. Pat. No.6,951,879, issued Oct. 4, 2005, which is now allowed. The entirecontents of the above-identified applications are hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention is concerned with novel heteroaromates, theirmanufacture and their use as medicaments.

BACKGROUND OF THE INVENTION

The compounds of the present invention inhibit2,3-oxidosqualene-lanosterol cyclase (EC 5.4.99.) which is required forthe biosynthesis of cholesterol, ergosterol and other sterols. Causalrisk factors that directly promote the development of coronary andperipheral atherosclerosis include elevated low-density lipoproteincholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C),hypertension, cigarette smoking and diabetes mellitus. Other synergisticrisk factors include elevated concentrations of triglyceride (TG)-richlipoproteins, small, dense low-density lipoprotein particles,lipoprotein (a) (Lp(a)), and homocysteine. Predisposing risk factorsmodify the causal or conditional risk factors and thus affectatherogenesis indirectly. The predisposing risk factors are obesity,physical inactivity, family history of premature CVD, and male sex. Thestrong connection between coronary heart disease (CHD) and high LDL-Clevels in plasma, and the therapeutic advantage of lowering elevatedLDL-C levels are now well established (Gotto et al., Circulation 81,1990, 1721-1733; Stein et al., Nutr. Metab. Cardiovasc. Dis. 2, 1992,113-156; Illingworth, Med. Clin. North. Am. 84, 2000, 23-42).Cholesterol-rich, sometimes unstable, atherosclerotic plaques lead tothe occlusion of blood vessels resulting in an ischemia or an infarct.Studies with respect to primary prophylaxis have shown that a loweringof plasma LDL-C levels in plasma reduces the frequency of non-fatalincidences of CHD, while the overall morbidity remains unchanged. Thelowering of plasma LDL-C levels in patients with pre-established CHD(secondary intervention) reduces CHD mortality and morbidity;meta-analysis of different studies shows that this decrease isproportional to the reduction of the LDL-C (Ross et al., Arch. Intern.Med. 159, 1999, 1793-1802).

The clinical advantage of cholesterol lowering is greater for patientswith pre-established CHD than for asymptomatic persons withhypercholesterolemia. According to current guidelines, cholesterollowering treatment is recommended for patients who had survived amyocardial infarct or patients suffering from angina pectoris or anotheratherosclerotic disease, with a target LDL-C level of 100 mg/dl.

Preparations such as bile acid sequestrants, fibrates, nicotinic acid,probucol as well as statins, i.e. HMG-Co-A reductase inhibitors such assimvastatin and atorvastatin, are used for usual standard therapies. Thebest statins reduce plasma LDL-C effectively by at least 40%, and alsoplasma triglycerides, a synergistic risk factor, but less effectively.In contrast, fibrates reduce plasma triglycerides effectively, but notLDL-C. Combination of a statin and a fibrate proved to be veryefficacious in lowering LDL-C and triglycerides (Ellen and McPherson, J.Cardiol. 81, 1998, 60B-65B), but safety of such a combination remains anissue (Shepherd, Eur. Heart J. 16, 1995, 5-13). A single drug with amixed profile combining effective lowering of both LDL-C andtriglycerides would provide additional clinical benefit to asymptomaticand symptomatic patients.

In humans, statins are well tolerated at standard dosage, but reductionsin non-sterol intermediates in the cholesterol synthesis pathway, suchas isoprenoids and coenzyme Q, may be associated with adverse clinicalevents at high doses (Davignon et al., Can. J. Cardiol. 8, 1992,843-864; Pederson and Tobert, Drug Safety 14, 1996, 11-24).

This has stimulated the search for, and development of compounds thatinhibit cholesterol biosynthesis, yet act distal to the synthesis ofthese important, non-sterol intermediates. 2,3-oxidosqualene:lanosterolcyclase (OSC), a microsomal enzyme, represents a unique target for acholesterol-lowering drug (Morand et al., J. Lipid Res., 38, 1997,373-390; Mark et al., J. Lipid Res. 37, 1996, 148-158). OSC isdownstream of farnesyl-pyrophosphate, beyond the synthesis ofisoprenoids and coenzyme Q. In hamsters, pharmacologically active dosesof an OSC inhibitor showed no adverse side-effects, in contrast to astatin which reduced food-intake and body weight, and increased plasmabilirubin, liver weight and liver triglyceride content (Morand et al.,J. Lipid Res., 38, 1997, 373-390). The compounds described in EuropeanPatent Application No. 636 367, which inhibit OSC and which lower thetotal cholesterol in plasma, belong to these substances.

OSC inhibition does not trigger the overexpression of HMGR because of anindirect, negative feed-back regulatory mechanism involving theproduction of 24(S),25-epoxycholesterol (Peffley et al., Biochem.Pharmacol. 56, 1998, 439-449; Nelson et al., J. Biol. Chem. 256, 1981,1067-1068; Spencer et al., J. Biol. Chem. 260, 1985, 13391-13394; Paniniet al., J. Lipid Res. 27, 1986, 1190-1204; Ness et al., Arch. Biochem.Biophys. 308, 1994, 420-425). This negative feed-back regulatorymechanism is fundamental to the concept of OSC inhibition because (i) itpotentiates synergistically the primary inhibitory effect with anindirect down-regulation of HMGR, and (ii) it prevents the massiveaccumulation of the precursor monooxidosqualene in the liver. Inaddition, 24(S),25-epoxycholesterol was found to be one of the mostpotent agonists of the nuclear receptor LXR (Janowski et al., Proc.Natl. Acad. Sci. USA, 96, 1999, 266-271). Considering that24(S),25-epoxycholesterol is a by-product of inhibition of OSC it ishypothesized that the OSC inhibitors of the present invention could alsoindirectly activate LXR-dependent pathways such as (i)cholesterol-7alpha-hydroxylase to increase the consumption ofcholesterol via the bile acid route, (ii) expression of ABC proteinswith the potential to stimulate reverse cholesterol transport andincrease plasma HDL-C levels (Venkateswaran et al., J. Biol. Chem. 275,2000, 14700-14707; Costet et al., J. Biol. Chem. June 2000, in press;Ordovas, Nutr Rev 58, 2000, 76-79, Schmitz and Kaminsky, Front Biosci 6,2001, D505-D514), and/or inhibit intestinal cholesterol absorption(Mangelsdorf, XIIth International Symposium on Atherosclerosis,Stockholm, June 2000). In addition, possible cross talks between fattyacid and cholesterol metabolism mediated by liver LXR have beenhypothesized (Tobin et al., Mol. Endocrinol. 14, 2000, 741-752).

SUMMARY OF THE INVENTION

The present compounds of formula I inhibit OSC and therefore alsoinhibit the biosynthesis of cholesterol, ergosterol and other sterols,and reduce the plasma cholesterol levels. They can therefore be used inthe therapy and prophylaxis of hypercholesterolemia, hyperlipemia,arteriosclerosis and vascular diseases in general. Furthermore, they canbe used in the therapy and/or prevention of mycoses, parasiteinfections, gallstones, cholestatic liver disorders, tumors andhyperproliferative disorders, e.g. hyperproliferative skin and vasculardisorders. In addition, it has unexpectedly been found that thecompounds of the present invention can also be of therapeutic use toimprove glucose tolerance in order to treat and/or prevent relateddiseases such as diabetes. The compounds of the present inventionfurther exhibit improved pharmacological properties compared to knowncompounds.

In particular, the invention relates to compounds of the formula (I)

wherein

-   U is O or a lone pair,-   Y N, or CR¹,-   Z is S, or S(O₂),-   V is a) —CH═CH—, and m and n are 0, or-   b) —CH₂—, and m+n≦2, or-   c) O or NR², and m is 1 to 6, n is 1 to 6, m+n≦7, or m is 1 to 3, n    is 0, or-   d) S, and m is 1 to 7, n is 0 to 6, m+n≦7, or-   e) —C≡C—, and m is 0 to 7, n is 0 to 7, m+n is ≦7,-   Q is cycloalkyl, cycloalkyl-lower-alkyl, phenyl optionally    substituted by 1 to 3 substituents independently selected from the    group as defined for R³, or an alkyl, alkenyl or alkadienyl group    optionally substituted by OH,-   A¹ is hydrogen, lower-alkenyl, or lower-alkyl optionally substituted    with hydroxy, lower-alkoxy, or thio-lower-alkoxy,-   A² is cycloalkyl, cycloalkyl-lower-alkyl, lower-alkenyl,    lower-alkinyl, heteroaryl, or lower-alkyl optionally substituted    with halogen, hydroxy, lower-alkoxy, or thio-lower-alkoxy, or-   A¹ and A² are bonded to each other to form a ring and -A¹-A²- is    lower-alkylene, or lower-alkenylene, optionally substituted by R⁴,    in which one —CH₂— group of -A¹-A²- can optionally be replaced by a    NR⁵, S, or O, or -A¹-A²- is —CH═N═CH═CH— which can optionally be    substituted by lower-alkyl,-   A³ and A⁴ independently from each other are hydrogen or lower-alkyl,    or A³ and A⁴ are bonded to each other to form a ring together with    the carbon atom to which they are attached and -A³-A⁴- is —(CH₂)₂₋₅—    which can optionally be mono- or multiply-substituted by    lower-alkyl,-   X is hydrogen or one or more optional halogen and/or lower-alkyl    substituents,-   R¹ is hydrogen or lower-alkyl,-   R² is hydrogen or lower-alkyl,-   R³ is halogen, N(R⁶,R⁷), piperidyl, piperazinyl,    piperazinyl-ethanone, morpholinyl, CONH₂, CN, NO₂, CF₃, OH,    lower-alkoxy, thio-lower-alkoxy, or is lower-alkyl, lower-alkenyl,    or lower-alkinyl, optionally substituted with OH, SH or N(R⁸,R⁹),-   R⁴ is hydroxy, lower-alkyl, lower-alkoxy, or thio-lower-alkoxy,-   R⁵ is hydrogen, lower-alkyl, or lower-alkyl-carbonyl,-   R⁶ and R⁷ independently from each other are selected from the group    consisting of hydrogen, lower-alkyl, phenyl and benzyl,-   R⁸ and R⁹ independently from each other are selected from the group    consisting of hydrogen and lower-alkyl,    and pharmaceutically acceptable salts and/or pharmaceutically    acceptable esters of compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated the following definitions are set forth toillustrate and define the meaning and scope of the various terms used todescribe the invention herein.

In this specification the term “lower” is used to mean a groupconsisting of one to seven, preferably of one to four carbon atom(s).

The term “lone pair” refers to an unbound electron pair, in particularto the unbound electron pair of a nitrogen atom in e.g. an amine.

The term “halogen” refers to fluorine, chlorine, bromine and iodine,with fluorine, chlorine and bromine being preferred.

The term “alkyl”, alone or in combination with other groups, refers to abranched or straight-chain monovalent saturated aliphatic hydrocarbonradical of one to twenty carbon atoms, preferably one to sixteen carbonatoms, more preferably one to ten carbon atoms. Lower-alkyl groups asdefined below also are preferred alkyl groups. Alkyl groups can besubstituted e.g. with halogen, particularly with flourine or chlorine,hydroxy, lower-alkoxy, and/or lower-alkoxy-carbonyl.

The term “lower-alkyl”, alone or in combination with other groups,refers to a branched or straight-chain monovalent alkyl radical of oneto seven carbon atoms, preferably one to four carbon atoms. This term isfurther exemplified by such radicals as methyl, ethyl, n-propyl,isopropyl, n-butyl, s-butyl, t-butyl and the like. A lower-alkyl groupmay have a substitution pattern as described earlier in connection withthe term “alkyl”.

The term “cycloalkyl” refers to a monovalent carbocyclic radical of 3 to10 carbon atom(s), preferably 3 to 6 carbon atoms.

The term “alkoxy” refers to the group R′—O—, wherein R′ is an alkyl. Theterm “lower-alkoxy” refers to the group R′—O—, wherein R′ is alower-alkyl. The term “thio-alkoxy” refers to the group R′—S—, whereinR′ is an alkyl. The term “thio-lower-alkoxy” refers to the group R′—S—,wherein R′ is a lower-alkyl.

The term “alkenyl”, alone or in combination with other groups, standsfor a straight-chain or branched hydrocarbon residue comprising anolefinic bond and up to 20, preferably up to 16 carbon atoms, morepreferably up to 10 carbon atoms. Lower-alkenyl groups as describedbelow also are preferred alkenyl groups. The term “lower-alkenyl” refersto a straight-chain or branched hydrocarbon residue comprising anolefinic bond and up to 7, preferably up to 4 carbon atoms, such as e.g.2-propenyl. An alkenyl or lower-alkenyl group may have a substitutionpattern as described earlier in connection with the term “alkyl”.

The term “alkadienyl”, alone or in combination with other groups, standsfor a straight-chain or branched hydrocarbon residue comprising 2olefinic bonds and up to 20, preferably up to 16 carbon atoms, morepreferably up to 10 carbon atoms. Lower-alkadienyl groups as describedbelow also are preferred alkadienyl groups. The term “lower-alkadienyl”refers to a straight-chain or branched hydrocarbon residue comprising 2olefinic bonds and up to 7 carbon atoms. An alkadienyl orlower-alkadienyl group may have a substitution pattern as describedearlier in connection with the term “alkyl”.

The term “alkinyl”, alone or in combination with other groups, standsfor a straight-chain or branched hydrocarbon residue comprising a triplebond and up to 20, preferably up to 16 carbon atoms. The term“lower-alkinyl” refers to a straight-chain or branched hydrocarbonresidue comprising a triple bond and up to 7, preferably up to 4 carbonatoms, such as e.g. 2-propinyl. An alkinyl or lower-alkinyl group mayhave a substitution pattern as described earlier in connection with theterm “alkyl”.

The term “alkylene” refers to a straight chain or branched divalentsaturated aliphatic hydrocarbon group of 1 to 20 carbon atoms,preferably 1 to 16 carbon atoms. The term “lower-alkylene” refers to astraight chain or branched divalent saturated aliphatic hydrocarbongroup of 1 to 7, preferably 3 to 6 carbon atoms. An alkylene orlower-alkylene group may have a substitution pattern as describedearlier in connection with the term “alkyl”.

The term “alkenylene” refers to a straight chain or branched divalenthydrocarbon group comprising an olefinic bond and up to 20 carbon atoms,preferably up to 16 carbon atoms. The term “lower-alkenylene” refers toa straight chain or branched divalent hydrocarbon group comprising anolefinic bond and up to 7, preferably up to 6 C-atoms. An alkenylene orlower-alkenylene group may have a substitution pattern as describedearlier in connection with the term “alkyl”.

The term “aryl” relates to the phenyl or naphthyl group which canoptionally be mono- or multiply-substituted by lower-alkyl,dioxo-lower-alkylene (forming e.g. a benzodioxyl group), halogen,hydroxy, cyano, CF₃, NH₂, N(lower-alkyl)₂, aminocarbonyl, carboxy,nitro, lower-alkoxy, thio-lower-alkoxy, lower-alkylcarbonyl,lower-alkylcarbonyloxy, aryl, or aryloxy. Preferred substituents arelower-alkyl, lower-alkoxy, thio-lower-alkoxy, lower-alkyl-carbonyl,lower-alkoxycarbonyl, fluorine, chlorine, bromine, CN, CF₃, and/ordioxo-lower-alkylene. More preferred substituents are fluorine,chlorine, bromine and CF₃.

The term “heteroaryl” refers to an aromatic 5- or 6-membered ring whichcan comprise 1, 2 or 3 atoms selected from nitrogen, oxygen and/orsulphur such as furyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,thienyl, isoxazolyl, oxazolyl, imidazolyl, or pyrrolyl. A heteroarylgroup may have a substitution pattern as described earlier in connectionwith the term “aryl”.

The term “pharmaceutically acceptable salts” embraces salts of thecompounds of formula (I) with inorganic or organic acids such ashydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid,phosphoric acid, citric acid, formic acid, maleic acid, acetic acid,fumaric acid, succinic acid, tartaric acid, methanesulphonic acid,p-toluenesulphonic acid and the like, which are non toxic to livingorganisms. Preferred salts are formates, hydrochlorides andhydrobromides.

The term “pharmaceutically acceptable esters” embraces esters of thecompounds of formula (I), in which hydroxy groups have been converted tothe corresponding esters with inorganic or organic acids such as nitricacid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleicacid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid,p-toluenesulphonic acid and the like, which are non toxic to livingorganisms.

In detail, the present invention relates to compounds of formula (I)

wherein

-   U is O or a lone pair,-   Y N, or CR¹,-   Z is S, or S(O₂),-   V is a) —CH═CH—, and m and n are 0, or-   b) —CH₂—, and m+n≦2, or-   c) O or NR², and m is 1 to 6, n is 1 to 6, m+n≦7, or m is 1 to 3, n    is 0, or-   d) S, and m is 1 to 7, n is 0 to 6, m+n≦7, or-   e) —C≡C—, and m is 0 to 7, n is 0 to 7, m+n is ≦7,-   Q is cycloalkyl, cycloalkyl-lower-alkyl, phenyl optionally    substituted by 1 to 3 substituents independently selected from the    group as defined for R³, or an alkyl, alkenyl or alkadienyl group    optionally substituted by OH,-   A¹ is hydrogen, lower-alkenyl, or lower-alkyl optionally substituted    with hydroxy, lower-alkoxy, or thio-lower-alkoxy,-   A² is cycloalkyl, cycloalkyl-lower-alkyl, lower-alkenyl,    lower-alkinyl, heteroaryl, or lower-alkyl optionally substituted    with halogen, hydroxy, lower-alkoxy, or thio-lower-alkoxy, or-   A¹ and A² are bonded to each other to form a ring and -A¹-A²- is    lower-alkylene, or lower-alkenylene, optionally substituted by R⁴,    in which one —CH₂— group of-   -A¹-A²- can optionally be replaced by a NR⁵, S, or O, or -A¹-A²- is-   —CH═N═CH═CH— which can optionally be substituted by lower-alkyl,-   A³ and A⁴ independently from each other are hydrogen or lower-alkyl,    or-   A³ and A⁴ are bonded to each other to form a ring together with the    carbon atom to which they are attached and -A³-A⁴- is —(CH₂)₂₋₅—    which can optionally be mono- or multiply-substituted by    lower-alkyl,-   X is hydrogen or one or more optional halogen and/or lower-alkyl    substituents,-   R¹ is hydrogen or lower-alkyl,-   R² is hydrogen or lower-alkyl,-   R³ is halogen, N(R⁶,R⁷), piperidyl, piperazinyl,    piperazinyl-ethanone, morpholinyl, CONH₂, CN, NO₂, CF₃, OH,    lower-alkoxy, thio-lower-alkoxy, or is lower-alkyl, lower-alkenyl,    or lower-alkinyl, optionally substituted with OH, SH or N(R⁸,R⁹),-   R⁴ is hydroxy, lower-alkyl, lower-alkoxy, or thio-lower-alkoxy,-   R⁵ is hydrogen, lower-alkyl, or lower-alkyl-carbonyl,-   R⁶ and R⁷ independently from each other are selected from the group    consisting of hydrogen, lower-alkyl, phenyl and benzyl,-   R⁸ and R⁹ independently from each other are selected from the group    consisting of hydrogen and lower-alkyl,    and pharmaceutically acceptable salts and/or pharmaceutically    acceptable esters thereof.

Preferred are compounds of formula (I) and/or pharmaceuticallyacceptable salts thereof. Other preferred embodiments relate tocompounds of formula (I) wherein U is a lone pair or to compounds offormula (I) wherein U is O.

Each of the definitions of V given above, a), b), c), d) and e),individually or in combination constitutes a preferred embodiment of thepresent invention. Compounds as described above in which V is O, m is 1to 6, n is 1 to 6, and m+n≦7 relate to a further preferred embodiment ofthe present invention. Another preferred embodiment of the presentinvention are compounds as described above, wherein V is O, m is 1 to 3,and n is O. Other preferred compounds are those, wherein V is —C≡C—, mis 0 to 2, and n is 0. Further preferred compounds are those, wherein Vis —CH₂— and m+n≦2.

Other preferred compounds of the present invention are those in which A¹represents hydrogen, methyl, or ethyl optionally substituted withhydroxy or methoxy. Another group of preferred compounds of the presentinvention are those in which A² represents methyl, n-propyl, i-propyl,2-propenyl, 2-propinyl, 1,1-dimethyl-2-propinyl, cyclopropyl-methylene,or ethyl optionally substituted with hydroxy or methoxy, with thosecompounds wherein A² represents methyl, ethyl, 2-hydroxy-ethyl,2-methoxy-ethyl, n-propyl, 2-propenyl, or cyclopropyl-methylene beingespecially preferred. If A² is heteroaryl, pyridyl and pyrimidinyl,which can optionally be substituted with lower-alkyl, preferably withmethyl, are preferred heteroaryl groups. Further preferred compounds asdefined above are those wherein A² is 2-Methyl-pyrimidin-4-yl.

Compounds of formula (I), wherein A¹ and A² are bonded to each other toform a ring and -A¹-A²- is lower-alkylene, optionally substituted by R⁴,in which one —CH₂— group of -A¹-A²- can optionally be replaced by NR⁵ orO, wherein R⁴ is hydroxy, and R⁵ is lower-alkyl or lower-alkyl-carbonyl,or -A¹-A²- is —CH═N═CH═CH—, are also preferred, with those compoundswherein said optional substituent R⁵ is methyl being particularlypreferred. If -A¹-A²- is —CH═N═CH═CH— which can optionally besubstituted by lower-alkyl, —CH═N═CH═CH— is preferably substituted bymethyl. In compounds wherein -A¹-A²- is —CH═N═CH═CH—, A¹ and A²,together with the nitrogen atom to which they are bound, form animidazol ring. In compounds wherein A¹ and A² are bonded to each otherto form a ring, said ring is preferably a 4-, 5-, or 6-membered ringsuch as e.g. piperidinyl or pyrrolidinyl. Compounds, wherein -A¹-A²- is—(CH₂)₅— are also preferred.

A further preferred embodiment of the present invention relates tocompounds of formula (I), wherein A³ and/or A⁴ represent hydrogen. Inaddition, compounds of formula (I) as defined above, wherein A³ and/orA⁴ represent methyl, relate to a preferred embodiment of the presentinvention. Compounds of formula (I) as defined above, wherein A³ and A⁴are bonded to each other to form a cyclopentyl-ring or a cyclohexyl-ringtogether with the carbon atom to which they are attached and -A³-A⁴- is—(CH₂)₄— or —(CH₂)₅— respectively represent another preferred embodimentof the present invention. The term —(CH₂)₂₋₅— denotes the groups—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄— and —(CH₂)₅—.

In addition, compounds as described before, wherein Y is CR¹ and R¹ ismethyl, are preferred. Furthermore, compounds in which Y is N relate toa preferred embodiment of the present invention. Other preferredcompounds are those, wherein Z is S. Compounds, wherein Z is SO₂ arealso preferred.

Compounds of formula (I), wherein Q is phenyl optionally substituted by1 to 3 substituents independently selected from the group as defined forR³, or an alkyl or alkenyl group optionally substituted by OH, whereinR³ is as defined above, represent a preferred embodiment of the presentinvention, with those compounds wherein Q is phenyl optionallysubstituted by 1 to 3 substituents independently selected from the groupas defined for R³, wherein R³ is fluorine, chlorine, bromine, or CF₃being more preferred, and with those compounds wherein Q is4-chloro-phenyl, 4-bromo-phenyl, or 4-trifluoromethyl-phenyl beingparticularly preferred. Another preferred group relates to compoundswherein X is hydrogen.

Further preferred embodiments of the present invention are thosecompounds as defined above wherein V is not —CH₂— and/or not —CH═CH—.

Compounds of formula (I), in which A² is cycloalkyl,cycloalkyl-lower-alkyl, lower-alkenyl, lower-alkinyl, or lower-alkyloptionally substituted with hydroxy, lower-alkoxy, or thio-lower-alkoxy,are preferred. Further, compounds in which A¹ and A² are bonded to eachother to form a ring and -A¹-A²- is lower-alkylene, or lower-alkenylene,optionally substituted by R⁴, in which one —CH₂— group of -A¹-A²- canoptionally be replaced by a NR⁵, S, or O, are preferred. Further,compounds in which A³ and A⁴ are not bonded to each other, arepreferred. Compounds, in which R³ is halogen, NH₂, N(lower-alkyl)₂,CONH₂, CN, NO₂, CF₃, OH, lower-alkoxy, thio-lower-alkoxy, or islower-alkyl, lower-alkenyl, or lower-alkinyl, optionally substitutedwith OH, SH or NH₂, are also preferred.

Another preferred embodiment of the present invention relates tocompounds of formula (I)

wherein

-   U is O or a lone pair,-   Y N, or CR¹,-   Z is S, or S(O₂),-   V is a) —CH═CH—, and m and n are 0, or-   b) —CH₂—, and m+n≦2, or-   c) O or NR², and m is 1 to 6, n is 1 to 6, m+n≦7, or m is 1 to 3, n    is 0, or-   d) S, and m is 1 to 7, n is 0 to 6, m+n≦7, or-   e) —C≡C—, and m is 0 to 7, n is 0 to 7, m+n is ≦7,-   Q is cycloalkyl, cycloalkyl-lower-alkyl, phenyl optionally    substituted by 1 to 3 substituents independently selected from the    group as defined for R³, or an alkyl, alkenyl or alkadienyl group    optionally substituted by OH,-   A¹ is hydrogen, lower-alkenyl, or lower-alkyl optionally substituted    with hydroxy, lower-alkoxy, or thio-lower-alkoxy,-   A² is cycloalkyl, cycloalkyl-lower-alkyl, lower-alkenyl,    lower-alkinyl, or lower-alkyl optionally substituted with hydroxy,    lower-alkoxy, or thio-lower-alkoxy, or-   A¹ and A² are bonded to each other to form a ring and -A¹-A²- is    lower-alkylene, or lower-alkenylene, optionally substituted by R⁴,    in which one —CH₂— group of-   -A¹-A²- can optionally be replaced by a NR⁵, S, or O,-   A³ and A⁴ independently from each other are hydrogen or lower-alkyl,-   X is hydrogen or one or more optional halogen and/or lower-alkyl    substituents,-   R¹ is hydrogen or lower-alkyl,-   R² is hydrogen or lower-alkyl,-   R³ is halogen, NH₂, N(lower-alkyl)₂, CONH₂, CN, NO₂, CF₃, OH,    lower-alkoxy, thio-lower-alkoxy, or is lower-alkyl, lower-alkenyl,    or lower-alkinyl, optionally substituted with OH, SH or NH₂,-   R⁴ is hydroxy, lower-alkyl, lower-alkoxy, or thio-lower-alkoxy,-   R⁵ is hydrogen, lower-alkyl, or lower-alkyl-carbonyl,    and pharmaceutically acceptable salts and/or pharmaceutically    acceptable esters thereof.

Preferred compounds of general formula (I) are those selected from thegroup consisting of

-   Allyl-[2-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethyl]-methyl-amine,-   [2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethyl]-dimethyl-amine,-   Allyl-[3-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-methyl-amine,-   [3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-dimethyl-amine,-   Allyl-[4-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-methyl-amine,-   [4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-dimethyl-amine,-   2-[[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-methyl-amino]-ethanol,-   2-[[3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-methyl-amino]-ethanol,-   2-[[2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethyl]-methyl-amino]-ethanol,-   [4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-(2-methoxy-ethyl)-methyl-amine,-   [3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-(2-methoxy-ethyl)-methyl-amine,-   [2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethyl]-(2-methoxy-ethyl)-methyl-amine,-   3-(4-Bromo-phenyl)-6-(4-morpholin-4-yl-butoxy)-benzo[d]isothiazole,-   3-(4-Bromo-phenyl)-6-(3-morpholin-4-yl-propoxy)-benzo[d]isothiazole,-   3-(4-Bromo-phenyl)-6-(2-morpholin-4-yl-ethoxy)-benzo[d]isothiazole,-   2-[[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-ethyl-amino]-ethanol,-   2-[[3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-ethyl-amino]-ethanol,-   2-[[2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethyl]-ethyl-amino]-ethanol,-   3-(4-Bromo-phenyl)-6-(4-pyrrolidin-1-yl-butoxy)-benzo[d]isothiazole,-   3-(4-Bromo-phenyl)-6-(3-pyrrolidin-1-yl-propoxy)-benzo[d]isothiazole,-   3-(4-Bromo-phenyl)-6-(2-pyrrolidin-1-yl-ethoxy)-benzo[d]isothiazole,-   6-(4-Azetidin-1-yl-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole,-   6-(3-Azetidin-1-yl-propoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole,-   6-(2-Azetidin-1-yl-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole,-   2-({4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amino)-ethanol,-   {4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine,-   4-{4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-morpholine,-   2-({4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-amino)-ethanol,-   1-{4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-pyrrolidine,-   1-{4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-azetidine,-   {4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-isopropyl-methyl-amine,-   {4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-diethyl-amine,-   {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine,-   Allyl-{4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-amine,-   2-({4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanol,-   6-(4-Azetidin-1-yl-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole,-   3-(4-Chloro-phenyl)-6-(4-piperidin-1-yl-butoxy)-benzo[d]isothiazole,-   {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine,-   Allyl-(3-[3-(4-bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-propyl)-methyl-amine,-   Allyl-(4-[3-(4-bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl)-methyl-amine,-   (3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-propyl)-dimethyl-amine,-   (4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl)-dimethyl-amine,-   6-(3-Azetidin-1-yl-propoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole    1,1-dioxide,-   6-(4-Azetidin-1-yl-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole    1,1-dioxide,-   {3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-propyl}-methyl-propyl-amine,-   {4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-propyl-amine,-   2-({3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-propyl}-ethyl-amino)-ethanol,-   2-({4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanol,-   {3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-propyl}-diethyl-amine,-   {4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-diethyl-amine,-   {3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-propyl}-(2-methoxy-ethyl)-methyl-amine,-   {4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine,-   2-({3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-propyl}-methyl-amino)-ethanol,-   2-({4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-amino)-ethanol,-   {3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-propyl}-ethyl-(2-methoxy-ethyl)-amine,-   {4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine,-   {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-diethyl-amine,-   {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-cyclopropylmethyl-methyl-amine,-   {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-isopropyl-methyl-amine,-   3-(4-Chloro-phenyl)-6-(4-pyrrolidin-1-yl-butoxy)-benzo[d]isothiazole,-   “{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine,-   2-({4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-amino)-ethanol,-   (3R)-1-{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-pyrrolidin-3-ol,-   2-[{3-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-(2-hydroxy-ethyl)-amino]-ethanol,-   {3-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-bis-(2-methoxy-ethyl)-amine,-   2-[{4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol,-   {4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-bis-(2-methoxy-ethyl)-amine,-   2-[[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-(2-hydroxy-ethyl)-amino]-ethanol,-   [4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-bis-(2-methoxy-ethyl)-amine,-   2-[[3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-(2-hydroxy-ethyl)-amino]-ethanol,-   [3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-bis-(2-methoxy-ethyl)-amine,-   [3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-ethyl-(2-methoxy-ethyl)-amine,-   3-(4-Chloro-phenyl)-6-(4-piperidin-1-yl-butoxy)-benzo[d]isothiazole    1,1-dioxide,-   Allyl-{4-[3-(4-chloro-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-amine,-   6-(4-Azetidin-1-yl-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole    1,1-dioxide,-   {4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine,-   2-({4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanol,-   {4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-diethyl-amine,-   2-({4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-amino)-ethanol,-   {4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine,-   3-(4-Chloro-phenyl)-6-(4-pyrrolidin-1-yl-butoxy)-benzo[d]isothiazole    1,1-dioxide,-   1-{4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-pyrrolidin-3-ol,-   {4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-isopropyl-methyl-amine,-   {4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-cyclopropylmethyl-methyl-amine,-   (4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl)-bis-(2-methoxy-ethyl)-amine,-   {4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-dimethyl-amine N-oxide,-   {4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine    N-oxide,-   (4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl)-bis-(2-methoxy-ethyl)-amine    N-oxide,-   Allyl-{3-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-methyl-amine,-   2-({3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-ethyl-amino)-ethanol,-   Allyl-{5-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-methyl-amine,-   {5-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-dimethyl-amine,-   2-({5-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-methyl-amino)-ethanol,-   {5-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-(2-methoxy-ethyl)-methyl-amine,-   2-({5-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-ethyl-amino)-ethanol,-   6-(5-Azetidin-1-yl-pent-1-ynyl)-3-(4-bromo-phenyl)-benzo[d]isothiazole,-   Diethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amine,-   6-(4-Piperidin-1-yl-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole,-   Allyl-methyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amine,-   6-(4-Azetidin-1-yl-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole,-   2-(Ethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanol,-   2-((2-Hydroxy-ethyl)-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanol,-   Dimethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amine,-   2-[{3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-(2-hydroxy-ethyl)-amino]-ethanol,-   Allyl-{3-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-methyl-amine,-   Allyl-{4-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amine,-   {3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-dimethyl-amine,-   {4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-dimethyl-amine,-   2-({3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-methyl-amino)-ethanol,-   2-({4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amino)-ethanol,-   {3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-(2-methoxy-ethyl)-methyl-amine,-   {4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine,-   2-(Ethyl-{3-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-amino)-ethanol,-   2-(Ethyl-{4-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-amino)-ethanol,-   Ethyl-{3-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-(2-methoxy-ethyl)-amine,-   Ethyl-{4-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-methoxy-ethyl)-amine,-   2-[{3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-(2-hydroxy-ethyl)-amino]-ethanol,-   2-[{4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol,-   {3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-bis-(2-methoxy-ethyl)-amine,-   {4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-bis-(2-methoxy-ethyl)-amine,-   1-{3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-pyrrolidine,-   1-{4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-pyrrolidine,-   1-{3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-azetidine,-   1-{4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-azetidine,-   Allyl-{4-[1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-amine,-   2-({4-[1,1-Dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanol,-   {4-[1,1-Dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-diethyl-amine,-   {4-[1,1-Dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-dimethyl-amine,-   6-(4-Piperidin-1-yl-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole    1,1-dioxide,-   6-(4-Azetidin-1-yl-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole    1,1-dioxide,-   2-[{4-[1,1-Dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol,-   {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-(1,1-dimethyl-prop-2-ynyl)-amine,-   2-{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butylamino}-ethanol,-   {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-prop-2-ynyl-amine,-   {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-prop-2-ynyl-amine,-   6-(4-Azetidin-1-yl-but-1-ynyl)-3-(4-bromo-phenyl)-benzo[d]isothiazole,-   2-({4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-methyl-amino)-ethanol,-   2-({3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-methyl-amino)-ethanol,-   2-({3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-ethyl-amino)-ethanol,-   Allyl-{3-[3-(4-bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-propyl}-methyl-amine,-   Allyl-{4-[3-(4-bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amine,-   {3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-propyl}-dimethyl-amine,-   2-({3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-propyl}-methyl-amino)-ethanol,-   2-({4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amino)-ethanol,-   2-({3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-propyl}-ethyl-amino)-ethanol,-   2-({4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-amino)-ethanol,-   {3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-propyl}-(2-methoxy-ethyl)-methyl-amine,-   {4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine,-   1-{3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-propyl}-azetidine,-   1-{4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-azetidine,-   Allyl-methyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amine,-   2-(Methyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amino)-ethanol,-   6-(5-Azetidin-1-yl-pent-1-ynyl)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole,-   (2-Methoxy-ethyl)-methyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amine,-   Dimethyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amine,-   {5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-dimethyl-amine,-   3-(4-Chloro-phenyl)-6-(5-piperidin-1-yl-pent-1-ynyl)-benzo[d]isothiazole,-   6-(5-Azetidin-1-yl-pent-1-ynyl)-3-(4-chloro-phenyl)-benzo[d]isothiazole,-   {4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-dimethyl-amine,-   Z-2-({3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-allyl}-ethyl-amino)-ethanol    acetate,-   Allyl-{5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-methyl-amine,-   {5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-diethyl-amine,-   2-[{5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-(2-hydroxy-ethyl)-amino]-ethanol,-   2-({5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-ethyl-amino)-ethanol,-   Allyl-methyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amine,-   2-(Methyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amino)-ethanol,-   2-(Ethyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amino)-ethanol,-   6-(3-Azetidin-1-yl-prop-1-ynyl)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole,-   (2-Methoxy-ethyl)-methyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amine,-   Dimethyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amine,-   3-(4-Bromo-phenyl)-6-(4-piperidin-1-yl-butoxy)-benzo[d]isothiazole,-   3-(4-Bromo-phenyl)-6-[4-(4-methyl-piperazin-1-yl)-butoxy]-benzo[d]isothiazole,-   1-(4-(4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl)-piperazin-1-yl)-ethanone,-   Allyl-{4-[3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amine,-   {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-dimethyl-amine,-   2-({4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-amino)-ethanol,-   {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-diethyl-amine,-   1-{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-piperidine,-   1-{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-azetidine,-   2-[{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol,-   {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-(2-methoxy-ethyl)-methyl-amine,-   {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-dimethyl-amine,-   Allyl-{4-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-methyl-amine,-   2-({4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-ethyl-amino)-ethanol,-   2-(Ethyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amino)-ethanol,-   2-({4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-ethyl-amino)-ethanol,-   {4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-propyl-amine,-   {3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-dimethyl-amine,-   {3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-propyl}-dimethyl-amine,-   2-(Ethyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl}-amino)-ethanol,-   Dimethyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl}-amine,-   2-(Methyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl}-amino)-ethanol,-   Allyl-{4-[3-(4-bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amine,-   {4-[3-(4-Bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-diethyl-amine,-   {4-[3-(4-Bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-methyl-propyl-amine,-   2-[{4-[3-(4-Bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol,-   2-({4-[3-(4-Bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-amino)-ethanol,-   {4-[3-(4-Bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine,-   1-{4-[3-(4-Bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-azetidine,-   Dimethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-amine,-   Allyl-methyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-amine,-   2-(Ethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-amino)-ethanol,-   2-(Methyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-amino)-ethanol,-   Allyl-{4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-methyl-amine,-   {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-diethyl-amine,-   {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-methyl-propyl-amine,-   2-[{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol,-   2-({4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-ethyl-amino)-ethanol,-   {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-ethyl-(2-methoxy-ethyl)-amine,-   6-(4-Azetidin-1-yl-butyl)-3-(4-chloro-phenyl)-benzo[d]isothiazole,-   (2-Methoxy-ethyl)-methyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-amine,-   2-(Ethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-amino)-ethanol,-   Dimethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-amine,-   2-(Methyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-amino)-ethanol,-   2-({3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-propyl}-ethyl-amino)-ethanol,    and pharmaceutically acceptable salts and/or pharmaceutically    acceptable esters thereof.

Other preferred compounds of general formula (I) are those selected fromthe group consisting of

-   2-({5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-methyl-amino)-ethanol,-   2-(Ethyl-{5-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-amino)-ethanol,-   {5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-dimethyl-amine,-   Allyl-{5-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-methyl-amine,-   Ethyl-{5-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-(2-methoxy-ethyl)-amine,-   {5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-(2-methoxy-ethyl)-methyl-amine,-   2-(Ethyl-{4-[3-(4-ethynyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanol,-   2-(Ethyl-{4-[3-(4-ethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanol,-   2-((3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-1,1-dimethyl-prop-2-ynyl)-ethyl-amino)-ethanol,-   2-({4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanol    N-oxide,-   2-(Ethyl-{4-[3-(4-piperidin-1-yl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanol,-   2-(Ethyl-{4-[3-(4-morpholin-4-yl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanol,-   2-[Ethyl-(4-{3-[4-(methyl-phenyl-amino)-phenyl]-benzo[d]isothiazol-6-yloxy}-butyl)-amino]-ethanol,-   Allyl-{4-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-methyl-amine,-   {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-dimethyl-amine,-   2-({4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-methyl-amino)-ethanol,-   2-({4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-ethyl-amino)-ethanol,-   {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-ethyl-(2-methoxy-ethyl)-amine,-   {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-(2-methoxy-ethyl)-methyl-amine,-   2-{Ethyl-[4-(3-phenyl-benzo[d]isothiazol-6-yloxy)-butyl]-amino}-ethanol,-   2-(Ethyl-{4-[3-(4-piperazin-1-yl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanol,-   1-{4-[4-(6-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-benzo[d]isothiazol-3-yl)-phenyl]-piperazin-1-yl}-ethanone,-   2-({4-[3-(4-Benzylamino-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanol,-   2-({4-[3-(4-Fluoro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-amino)-ethanol,-   {4-[3-(4-Fluoro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine,-   Ethyl-{4-[3-(4-fluoro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-amine,-   2-(Ethyl-{4-[3-(4-fluoro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanol,-   2-{3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propylamino}-ethanol,-   {3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-methyl-prop-2-ynyl-amine,-   {3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-prop-2-ynyl-amine,-   3-(4-Bromo-phenyl)-6-(3-piperidin-1-yl-propoxy)-benzo[d]isothiazole,-   3-(4-Bromo-phenyl)-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzo[d]isothiazole,-   1-(4-{3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-piperazin-1-yl)-ethanone,-   2-({4-[3-(4-Amino-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanol,-   Allyl-{1,1-dimethyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d)    isothiazol-6-yl]-prop-2-ynyl}-methyl-amine,-   2-((1,1-Dimethyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl)-ethyl-amino)-ethanol,-   {1,1-Dimethyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-(2-methoxy-ethyl)-methyl-amine,-   {1,1-Dimethyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-ethyl-(2-methoxy-ethyl)-amine,-   2-(Ethyl-{1-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-ylethynyl]-cyclohexyl}-amino)-ethanol,-   {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-(2-fluoro-ethyl)-amine,-   Ethyl-(2-fluoro-ethyl)-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amine,-   2-[(4-{3-[4-(3-Dimethylamino-prop-1-ynyl)-phenyl]-benzo[d]isothiazol-6-yloxy}-butyl)-ethyl-amino]-ethanol,-   3-[4-(6-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-benzo[d]isothiazol-3-yl)-phenyl]-prop-2-yn-1-ol,-   2-[Ethyl-(4-{3-[4-(3-methylamino-prop-1-ynyl)-phenyl]-benzo[d]isothiazol-6-yloxy}-butyl)-amino]-ethanol,-   2-(Ethyl-{1-methyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amino)-ethanol,-   (2-Methoxy-ethyl)-methyl-{1-methyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amine,-   Ethyl-(2-methoxy-ethyl)-{1-methyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amine,-   Allyl-methyl-{1-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-ylethynyl]-cyclopentyl}-amine,-   {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amine,-   {3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-ethyl-amine,-   2-{Ethyl-[4-(3-methyl-benzo[d]isothiazol-6-yloxy)-butyl]-amino}-ethanol,-   Ethyl-(2-methoxy-ethyl)-[4-(3-methyl-benzo[d]isothiazol-6-yloxy)-butyl]-amine,-   {2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-1,1-dimethyl-ethyl}-dimethyl-amine,-   {2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-1-methyl-ethyl}-dimethyl-amine,-   1-{4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-piperidin-4-ol,-   {4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-propyl-amine,-   2-{4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butylamino}-ethanol,-   2-(Ethyl-{4-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-amino)-ethanol,-   Allyl-methyl-{4-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-amine,-   1-{4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-piperidine,-   {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine,-   {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-dimethyl-amine,-   2-(Ethyl-{4-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-amino)-ethanol,-   Diethyl-{4-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-amine,-   Methyl-{4-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-propyl-amine,-   Ethyl-(2-methoxy-ethyl)-{4-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-amine,-   2-((2-Hydroxy-ethyl)-{4-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-amino)-ethanol,-   Methyl-{3-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-prop-2-ynyl}-propyl-amine,-   2-(Ethyl-{3-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-prop-2-ynyl}-amino)-ethanol,-   Diethyl-{3-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-prop-2-ynyl}-amine,-   Allyl-methyl-{3-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-prop-2-ynyl}-amine,-   Allyl-methyl-{5-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-amine,-   Methyl-{5-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-propyl-amine,-   2-(Ethyl-{5-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-amino)-ethanol,-   Diethyl-{5-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-amine,-   1-{3-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-propyl}-azetidine,-   1-{3-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-propyl}-piperidin-4-ol,-   1-{3-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-propyl}-piperidine,-   1-{3-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-propyl}-pyrrolidine,-   2-(Ethyl-{3-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-propyl}-amino)-ethanol,-   Allyl-methyl-{3-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-propyl}-amine,-   Allyl-methyl-{4-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-butyl}-amine,-   2-(Ethyl-{4-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-butyl}-amino)-ethanol,-   2-{4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-butylamino}-ethanol,-   1-{4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-butyl}-piperidine,-   1-{4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-butyl}-piperidin-4-ol,-   {4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-butyl}-propyl-amine,-   2-(Ethyl-{3-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yl]-propyl}-amino)-ethanol,-   2-{3-[2-Methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yl]-propylamino}-ethanol,-   {3-[2-Methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yl]-propyl}-propyl-amine,-   1-{3-[2-Methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yl]-propyl}-piperidin-4-ol,-   1-{3-[2-Methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yl]-propyl}-piperidine,-   Allyl-methyl-{3-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yl]-propyl}-amine,-   2-(Ethyl-{4-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yl]-butyl}-amino)-ethanol,-   Allyl-methyl-{4-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yl]-butyl}-amine,-   1-{4-[2-Methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yl]-butyl}-piperidine,-   1-{4-[2-Methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yl]-butyl}-piperidin-4-ol,-   {4-[2-Methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yl]-butyl}-propyl-amine,-   2-{4-[2-Methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yl]-butylamino}-ethanol,-   2-(Ethyl-{5-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yl]-pent-4-ynyl}-amino)-ethanol,-   Methyl-{5-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yl]-pent-4-ynyl}-propyl-amine,-   Allyl-methyl-{5-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yl]-pent-4-ynyl}-amine,-   Diethyl-{5-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yl]-pent-4-ynyl}-amine,-   Methyl-{2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-amine,-   {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amine,-   Methyl-(2-methyl-pyrimidin-4-yl)-{2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-amine,-   Methyl-{2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-pyrimidin-4-yl-amine,-   (2-Methyl-pyrimidin-4-yl)-{2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-amine,-   {2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-pyrimidin-4-yl-amine,-   {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-methyl-(2-methyl-pyrimidin-4-yl)-amine,-   {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-methyl-pyrimidin-4-yl-amine,-   {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-(2-methyl-pyrimidin-4-yl)-amine,-   {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-pyrimidin-4-yl-amine,-   {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-methyl-pyridin-4-yl-amine,-   1-{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-1H-imidazole,    and-   1-{2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-1H-imidazole,    and pharmaceutically acceptable salts and/or pharmaceutically    acceptable esters thereof.

Particularly preferred compounds of general formula (I) are thoseselected from the group consisting of

-   2-({5-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-ethyl-amino)-ethanol,-   2-(Ethyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amino)-ethanol,-   2-[{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol,-   {5-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-dimethyl-amine,-   {4-[3-(4-Bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine,-   3-(4-Bromo-phenyl)-6-[4-(4-methyl-piperazin-1-yl)-butoxy]-benzo[d]isothiazole,-   {4-[3-(4-Bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-diethyl-amine, and-   Allyl-methyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amine,    and pharmaceutically acceptable salts and/or pharmaceutically    acceptable esters thereof.

Other particularly preferred compounds of general formula (I) are thoseselected from the group consisting of

-   2-[[3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-ethyl-amino]-ethanol,-   Dimethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amine,-   2-[[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-ethyl-amino]-ethanol,-   6-(3-Azetidin-1-yl-prop-1-ynyl)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole,-   2-(Ethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanol,-   2-[[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-(2-hydroxy-ethyl)-amino]-ethanol,-   {4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-cyclopropylmethyl-methyl-amine,    and-   Dimethyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amine,    and pharmaceutically acceptable salts and/or pharmaceutically    acceptable esters thereof.

Other particularly preferred compounds of general formula (I) are thoseselected from the group consisting of

-   {5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-diethyl-amine,-   2-({5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-ethyl-amino)-ethanol,-   Allyl-{4-[3-(4-bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amine,-   {4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl]-methyl-propyl-amine,-   2-[{4-[3-(4-Bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol,-   6-(5-Azetidin-1-yl-pent-1-ynyl)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole,    and-   2-(Ethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-amino)-ethanol,    and pharmaceutically acceptable salts and/or pharmaceutically    acceptable esters thereof.

Other particularly preferred compounds of general formula (I) are thoseselected from the group consisting of

-   {4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine,-   (4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-butyl)-dimethyl-amine, and-   {3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l    6-benzo[d]isothiazol-6-yloxy]-propyl}-diethyl-amine,    and pharmaceutically acceptable salts and/or pharmaceutically    acceptable esters thereof.

Other particularly preferred compounds of general formula (I) are thoseselected from the group consisting of

-   3-(4-Bromo-phenyl)-6-(3-piperidin-1-yl-propoxy)-benzo[d]isothiazole,-   2-(Ethyl-{4-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-butyl}-amino)-ethanol,-   2-(Ethyl-{1-methyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amino)-ethanol,-   Ethyl-(2-methoxy-ethyl)-{4-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l    6-benzo[b]thiophen-6-yloxy]-butyl}-amine,-   {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-ethyl-(2-methoxy-ethyl)-amine,-   2-(Ethyl-{3-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-propyl}-amino)-ethanol,-   2-((1,1-Dimethyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl)-ethyl-amino)-ethanol,-   2-((3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-1,1-dimethyl-prop-2-ynyl)-ethyl-amino)-ethanol,-   Methyl-(2-methyl-pyrimidin-4-yl)-{2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-amine,    and-   (2-Methyl-pyrimidin-4-yl)-{2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-amine,    and pharmaceutically acceptable salts and/or pharmaceutically    acceptable esters thereof.

Compounds of formula (I) can have one or more asymmetric carbon atomsand can exist in the form of optically pure enantiomers or as racemates.The invention embraces all of these forms.

It will be appreciated, that the compounds of general formula (I) inthis invention may be derivatized at functional groups to providederivatives which are capable of conversion back to the parent compoundin vivo.

Another particularly preferred embodiment of the present invention iscompounds of formula (VII)

wherein

-   Y N or CR¹,-   Z is S or S(O₂),-   V is O, CH₂, or C≡C,-   R³ is halogen or CF₃,-   m is 1, 2 or 3,-   A¹ is hydrogen, lower-alkyl or lower-alkoxy, and-   A² is lower alkyl, lower alkoxy, lower alkyl-lower alkoxy, lower    alkenyl, cycloalkyl, pyrimidine or pyrimidine-lower alkyl or-   A¹ and A² are bonded to each other to form a lower alkyl in which    one —CH₂— group is optionally replaced by a NR⁵,-   A³ is hydrogen or lower alkyl,-   A⁴ is hydrogen or lower-alkyl,-   R¹ is hydrogen or lower-alkyl,-   R² is hydrogen or lower-alkyl, and-   R⁵ is hydrogen or lower-alkyl;    pharmaceutically acceptable salts of compounds of formula (VII); and    pharmaceutically acceptable esters of compounds of formula (VII).

The present invention also relates to a process for the manufacture ofcompounds as described above, which process comprises

reacting a compound of formula (II)

with a compound (A¹,A²,U)N—C(A³,A⁴)—(CH₂)_(m)-M, wherein V is O, S orNR², M is mesylate, tosylate, triflate, Cl, Br or I, and X, Y, Z, Q, U,A¹, A², A³, A⁴, m, n and R² have the significances given above, orwherein HV is mesylate, tosylate, triflate, Cl, Br or I, and M is OH, SHor NHR², and R² has the significance given above,or b) reacting a compound of formula (III)

with a compound NHA¹,A², wherein M is mesylate, tosylate, triflate, Cl,Br or I, and A¹, A², A³, A⁴, V, X, Y, Z, Q, m and n are as definedabove,or c) reacting a compound of formula (IV)

with a compound (A¹,A²,U)N—C(A³,A⁴)—(CH₂)_(m)—C≡CH, wherein X, Y, Z, Q,U, A¹, A², A³, A⁴ and m are as defined above,or d) reacting a compound of formula (V)

with a compound (A¹,A²,U)N—C(A³,A⁴)—(CH₂)_(m)-M, wherein M is mesylate,tosylate, Cl, Br or I, and A¹, A², A³, A⁴, U, X, Y, Z, Q, m and n are asdefined above,or e) hydrogenating a compound of formula (VI)

wherein V is —C≡C—, and A¹, A², A³, A⁴, U, X, Y, Z, Q, m and n are asdefined above,and optionally converting a compound of formula (I) as defined above,wherein U is a lone pair, to a corresponding compound wherein U is O.

The invention further relates to compounds of formula (I) as definedabove, when manufactured according to a process as defined above.

As described above, the compounds of formula (I) of the presentinvention can be used for the treatment and/or prophylaxis of diseaseswhich are associated with OSC such as hypercholesterolemia,hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasiteinfections and gallstones, and/or treatment and/or prophylaxis ofimpaired glucose tolerance, diabetes, tumors and/or hyperproliferativedisorders, preferably for the treatment and/or prophylaxis ofhypercholesterolemia and/or hyperlipemia. Hyperproliferative skin andvascular disorders particularly come into consideration ashyperproliferative disorders.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptablecarrier and/or adjuvant.

Further, the invention relates to compounds as defined above for use astherapeutic active substances, particularly as therapeutic activesubstances for the treatment and/or prophylaxis of diseases which areassociated with OSC such as hypercholesterolemia, hyperlipemia,arteriosclerosis, vascular diseases, mycoses, parasite infections,gallstones, tumors and/or hyperproliferative disorders, and/or treatmentand/or prophylaxis of impaired glucose tolerance and diabetes,preferably for the treatment and/or prophylaxis of hypercholesterolemiaand/or hyperlipemia.

In another embodiment, the invention relates to a method for thetreatment and/or prophylaxis of diseases which are associated with OSCsuch as hypercholesterolemia, hyperlipemia, arteriosclerosis, vasculardiseases, mycoses, parasite infections, gallstones, tumors and/orhyperproliferative disorders, and/or treatment and/or prophylaxis ofimpaired glucose tolerance and diabetes, preferably for the treatmentand/or prophylaxis of hypercholesterolemia and/or hyperlipemia, whichmethod comprises administering a compound as defined above to a humanbeing or animal.

The invention further relates to the use of compounds as defined abovefor the treatment and/or prophylaxis of diseases which are associatedwith OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis,vascular diseases, mycoses, parasite infections, gallstones, tumorsand/or hyperproliferative disorders, and/or treatment and/or prophylaxisof impaired glucose tolerance and diabetes, preferably for the treatmentand/or prophylaxis of hypercholesterolemia and/or hyperlipemia.

In addition, the invention relates to the use of compounds as definedabove for the preparation of medicaments for the treatment and/orprophylaxis of diseases which are associated with OSC such ashypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases,mycoses, parasite infections, gallstones, tumors and/orhyperproliferative disorders, and/or treatment and/or prophylaxis ofimpaired glucose tolerance and diabetes, preferably for the treatmentand/or prophylaxis of hypercholesterolemia and/or hyperlipemia. Suchmedicaments comprise a compound as defined above.

The compounds of formula (I) can be manufactured by the methods givenbelow, by the methods given in the examples or by analogous methods.Appropriate reaction conditions for the individual reaction steps areknown to the person skilled in the art. Starting materials are eithercommercially available or can be prepared by methods analogous to themethods given in the examples or by methods known in the art.

Scheme 1:

For compounds which are benzo[d]isothiazole derivatives, the synthesisstarts from a suitable protected fluoro-substituted aromatic system 1(V═O or NR², and n=0-6, or V═S and n=0) and an acid chloride 2 which isconverted under Friedel-Crafts conditions with a Lewis acid such asaluminium chloride to the phenone 3 (step a). The starting materials 1are either commercially available or can be obtained by methods known inthe art, e.g. from the corresponding acids. The transformation to theheterocyclic system may be achieved by reacting the fluoride 3 with e.g.benzylmercaptane in the presence of potassium tert.butylate in THF atRT, treating the benzylthio ether 4 obtained with sulfuryl chloride inmethylene chloride (at 0° C.) and cyclizing the resulting intermediatein THF with a solution of ammonia in ethanol to 5, as described inEuropean Patent application 778271 (steps b and c). In case ofmethoxyphenylether 5 (n=0, V-PG=OMe) treatment with boron tribromide inmethylene chloride at −78° C. to RT or with 62% aqueous HBr in aceticacid at reflux gives phenol 6. For V═NR² or V═O and n>0, deprotectionusing procedures known in the art (step d) gives the free HV-buildingblock 6.

Oxidation of a suitable protected benzo[d]isothiazols 5 (V═O or NR², andn=0-6, or V═S and n=0) may be effected with e.g. KMnO₄ on silicagel inCH₂Cl₂ at 50° C. to yield the corresponding benzo[d]isothiazole1,1-dioxide. For V═S and n>0, the sulfur is introduced in a later step(see Scheme 4).

Scheme 2:

For compounds which are benzo[b]thiophene derivatives, the synthesisstarts from a suitable protected thiol 1 and α-bromoacetophenonederivative 2 which are converted to the thioether 3 by treatment withKOH in EtOH at 0° C. to RT (step a). The starting materials 1 are eithercommercially available or can be obtained by methods known in the art,e.g. from the corresponding acids. The cyclization can be carried out byheating the compound 3 in polyphosphoric acid to 80-100° C. or bytreatment with BF₃.Et₂O to give benzo[b]thiophene 4 (step b).

In the case of methoxyphenylether 4 (n=0, V-PG=OMe), treatment withboron tribromide in methylene chloride at −78° C. to RT or with 62%aqueous HBr in acetic acid at reflux gives phenol 5. For V═S, NR² or V═Oand n>0, deprotection using procedures known in the art (step d) givesthe free HV-building block 5.

Oxidation of a suitable protected benzo[b]thiophene 4 (V═O or NR², andn=0-6, or V═S and n=0) may be effected with e.g. sodium perborate inacetic acid at 50° C. yield the corresponding benzo[b]thiophene1,1-dioxide 4.

For V═S and n>0, the sulfur is introduced in a later step (see Scheme4). Alternatively compound of the formula 5 may be prepared as describedpreviously in European Patent application 778271.

Scheme 3:

Scheme 3 shows the synthesis of amino-VH sidechain 4 that may be usedfor the synthesis of compounds with the corresponding V-spacers (V═NR²,S, or O). α,ω-dihaloalkane or mesyl-alkanyl-halogenide 1 may be treatedwith a suitable protected amine (HNR²-PG, PG=protecting group, e.g. BOC)in DMA or a thiol (HS-PG) e.g., triphenylmethanethiol in the presence ofNaH in DMA to give the compound 2 (step a). Treatment with the amineA¹A²NH yields the S- or N-protected amine 3 (step b) and in the case ofα,ω-haloalkanol 1 directly amino-alcohol 4. N-deprotection withprocedures known in the art e.g. TFA in CH₂Cl₂ gives the amine sidechain 4 (step c). The deprotection of the thiol moiety in 3 may beachieved with TFA/triisopropylsilane in CH₂Cl₂ at 0° C. to RT to yieldthe aminothiol 4 (step c). Aminoalkanol 4 can further be transformed tomesylate 5 (step d).

Scheme 4:

Alkylation of the phenol 1 (V═O, S, n=0) in acetone with K₂CO₃ and asuitable dihaloalkane (halogen is here represented by bromine, but canalso be chlorine or iodine. It is also possible to use mesylates ortosylates instead of halogenides) at reflux yields halogenide 2(reaction step a). For the preparation of derivatives 2 (V═O, n>0), thealcohol 1 can be treated with α,ω-dihaloalkanes under phase transferconditions e.g. α,ω-dihaloalkanes, NaOH, nBu₄NHSO₄. For V═S, O orNR²-PG, the derivative 1 may be treated with α,ω-dihaloalkane in thepresence of NaH in DMF 0° C. to RT to yield bromide 2. For shorteralkanes (m=1 or 2), the method of choice is the in situ generation ofthe haloalkane-triflate (from the corresponding haloalkanol withtrifluoromethansulfonic anhydride/2,6-di-tert-butylpyridine in CH₂Cl₂ at0° C.). This haloalkane-triflate may then be reacted with 1 in thepresence of a base such as with 2,6-di-tert-butylpyridine as base innitromethane at 60° C. to yield bromide 2 [analogously to a procedure ofBelostotskii, Anatoly M.; Hassner, Alfred. Synthetic methods. 41.Etherification of hydroxysteroids via triflates. Tetrahedron Lett.(1994), 35(28), 5075]. Compound 2 can be converted (reaction step b) tothe amine 3 with an excess of the corresponding amine NHA¹A² in asuitable solvent such as DMA, DMF, MeOH at RT or 50-65° C. or with amineNHA¹A², sodium hydride in DMF, DMA or THF. Alternatively, the compound 1may be transferred to the amine 3 by attaching the pre-assembledfragment A¹A²NC(A³A⁴)(CH₂)_(m)—OMes/halogenide, which can be synthesizedby known methods (shown e.g in Scheme 3), using alkylating conditions(step d). Heteroaromate 1 (V═O, n>0) can also be mesylated 1 (V═OMes)and then reacted with A¹A²NC(A³A⁴)(CH₂)_(m)—VH (synthesis describedScheme 3) in e.g. DMF with NaH as base to give 3 (with V═O, S, NR²).

Amine 3 may be converted to a salt or to the N-oxide 4 (step c). For theformation of N-oxide 4 (V═O) a mixture of hydrogen peroxide urea adductand phthalic anhydride in CH₂Cl₂ at RT may be used. For the preparationof the N-oxides 4 (V═S or NR²) step e may be performed: Oxidation of thepre-assembled fragment A¹A²NC(A³A⁴)(CH₂)_(n)—OMes/halogenide to thecorresponding N-oxide derivative, followed by alkylation of the compound1.

Oxidation of 2 (V═O or NR²) may be effected with e.g. KMnO₄ on silicagelin CH₂Cl₂ at 50° C. for benzo[d]isothiazols to give the correspondingbenzo[d]isothiazole 1,1-dioxide 5. In the case of benzo[b]thiophene 2,oxidation with sodium perborate in acetic acid at 50° C. givesbenzo[b]thiophene 1,1-dioxide 5. Bromide 5 can be transformed to 3 and 4as described for bromide 2.

If A²=H, heteroaromatic moieties A² may be introduced by treatment withhalo heteroaromatics in the presence of Huenig's base in DMF (Ger.Offen. (1990), DE3905364 A1). Alternatively, Buchwald conditions e.g.Pd(OAc)₂, 2-(Dicyclohexylphosphino) biphenyl, NaOtBu in toluene might beapplied (John P. Wolfe, Hiroshi Tomori, Joseph P. Sadighi, Jingjun Yin,and Stephen L. Buchwald, J. Org. Chem., 65 (4), 1158-1174, 2000).

Amine 3 may be further modified. For Q=methyl, deprotonation with e.g.lithium diisopropylamide in THF at −78° C. and then treatment with abromide BrCH₂—R⁷ or aldehyde HC(O)—R⁷, wherein R⁷ is an alkyl, alkenylor alkadienyl group with up to 12 C atoms, may yield the correspondingcompound 3 in which Q stands for CH₂CH₂—R⁷ or CH₂CH(OH)—R⁷.

For an amine 3 or also starting compound 1 in which Q is a halo- orhydroxy-substituted aromatic system (in case of the later, thecorresponding triflate may be synthesized) the corresponding alkyne,alkyl, alkene, amine, alkoxy or thioalkoxy substituted derivative can besynthesized employing Sonogashira reaction or palladium catalyzedamination, C—O or C—S coupling reactions. For the Sonogashira reactionof the arylhalogenide or aryltriflate may be treated with a suitablealkynes or alkynol in THF in the presence of a base such astriethylamine or piperidine with a catalytic amount of e.g.Pd(PPh₃)₄/CuI or Pd(OAc)₂/CuI or PdCl₂(PPh₃)₂/CuI at 45° C. to 80°.These alkynes can then selectively be reduced. The introduction of anamine moiety may be achieved using primary or secondary amines and thearylhalogenide or aryltriflate using methods developed by Buchwald e.g.tris(Dibenzylideneacetone)dipalladium, 2(di-tertbutylphosphino)Biphenylin toluene and Natrium tert-butylat as base to give the newlysubstituted 3 [e.g. Wolfe, John P.; Tomori, Hiroshi; Sadighi, Joseph P.;Yin, Jingjun; Buchwald, Stephen L. Simple, efficient catalyst system forthe palladium-catalyzed amination of aryl chlorides, bromides, andtriflates. J. Org. Chem. (2000), 65(4), 1158-1174].

For the oxygen analogues see for example Palucki, Michael; Wolfe, JohnP.; Buchwald, Stephen L. Palladium-Catalyzed IntermolecularCarbon-Oxygen Bond Formation: A New Synthesis of Aryl Ethers. J. Am.Chem. Soc. (1997), 119(14), 3395-3396. These newly substituted amines 3can then again be transformed to compound 4. For the preparation of theN-oxides 4 (V═S or NR²) step e may be performed: Oxidation of thepre-assembled fragment A¹A²NC(A³A⁴)(CH₂)_(m)—OMes/halogenide to thecorresponding N-oxide derivative, followed by alkylation of the compound1.

Scheme 5:

In Scheme 5, the preparation of compounds of formula 6, in which Vrepresents —CH₂—, —CH═CH— or —C≡C— is outlined starting fromhydroxyphenyl derivative 1, which may be transformed to the triflate 2in pyridine with trifluoromethanesulfonic anhydride at 0° C. to RT(reaction step a). Sonogashira-coupling (reaction step b) of thetriflate 2 and a suitable alkynol or alkynechloride in piperidine withPd(PPh₃)₄/CuI at 45° C. to 80° C. in analogy to a literature procedureyields alcohol 3a or chloride 3b [Stara, Irena G.; Stary, Ivo;Kollarovic, Adrian; Teply, Filip; Saman, David; Fiedler, Pavel. Couplingreactions of halobenzenes with alkynes. The synthesis ofphenylacetylenes and symmetrical or unsymmetrical1,2-diphenylacetylenes. Collect. Czech. Chem. Commun. (1999), 64(4),649-672.]. In case of Q=Bromo or Iodo-substituted aromatic system,triflate 2 is dissolved in THF with PdCl₂(PPh₃)₂ as catalyst and alkynolor alkynechloride, triphenylphosphine, triethylamine and a catalyticamount of CuI to give alkyne 3a or 3b. Mesylation for alcohol 3a withmethanesulfonylchloride e.g. in pyridine with DMAP (reaction step c) andsubsequent amination (reaction step d) of the resulting mesylate 4 witha suitable amine NHA¹A² in DMA at RT or as described in Scheme 4 yieldsthe amine 5. Alcohol 3a can also be treated with trifluoromethanesulfonic acid anhydride and Huenig's base at −15° C. in CH₂Cl₂ (in situgeneration of the corresponding triflate) followed by treatment with thecorresponding amine NHA¹A² at −15° C. to RT. This is especially themethod of choice for but-3-yn-1-ol-derivatives 3a. Chloride 3b can betransformed directly or via iodide (Finkelstein reaction) to the amine5, as described above (step d). Compounds 5 in which V is —CH₂— or—CH═CH— can be obtained by hydrogenation of compound 5 in EtOH withPt₂O.H₂O (yields the saturated analogue 5) or by selective hydrogenationwith other known methods (yields the double bond analogue 5).Optionally, the hydrogenation described above can be performed at anearlier stage e.g. the alcohol 3a or mesylate 4.

For compounds in which A³ and/or A⁴ are not H, the group A¹A²NC(A³A⁴C)[CH₂]_(m)-acetylene can be synthesised by known methods and attached tocompound 2 (Sonogashira-coupling), to yield the compounds of the presentinvention 5 (reaction step f).

Compounds of the formula 5 (n>0) may be synthesised by Swern oxidationof the alcohol 1 (V═O and n>0) to the corresponding aldehyde 7 (step g).The aldehyde 7 may be treated with triphenylphosphine,tetra-bromo-methane and triethylamine in CH₂Cl₂ at 0° C. to RT to yield2,2-Dibromo-vinyl derivative 8 (step h). Rearrangement with n-BuLi (ca1.6 M in hexane) in THF at −78° C., followed by reaction withformaldehyde (−78° C. to RT) leads to the propargyl alcohol 9a (step i,side chain extension through application of the Corey-Fuchs method),following conditions described in: Marshall, James A.; Bartley, Gary S.;Wallace, Eli M. Total Synthesis of the Pseudopterane (−)-Kallolide B,the Enantiomer of Natural (+)-Kallolide B. J. Org. Chem. (1996), 61(17),5729-5735; and Baker, Raymond; Boyes, Alastair L.; Swain, Christopher J.Synthesis of talaromycins A, B, C, and E. J. Chem. Soc., Perkin Trans. 1(1990), (5), 1415-21.

For longer side chains, the rearrangement is performed with n-BuLi (ca1.6 M in hexane) in THF at −78° C. as above, followed by addition of acosolvent such as DMPU and reaction with O-protected 1-bromo-alcohols orα-chloro-co-iodoalkane (e.g. 1-bromo-n-tetrahydro-pyaranyloxyalkane) toyield the O-protected compounds 9b or the chloro compound 9c (step i).O-protected compounds 9b can be deprotected to the corresponding alkynol9a (in MeOH at 50-60° C., in the presence of catalytic amount ofpyridinium toluene-4-sulfonate). Alcohol 9a can be reacted with Huenig'sbase/trifluoromethane sulfonic acid anhydride at −15° C. in CH₂Cl₂ (insitu generation of the corresponding triflate) followed by treatmentwith Huenig's base and the corresponding amine NHA¹A² at −15° C. to RTto give amine 5. Alternatively, mesylation of alcohol 9a withmethanesulfonylchloride, pyridine and DMAP in CH₂Cl₂ at 0° C. to RTgives mesylate 10. Conversion of the mesylate 10 or the chloride 9c (orthe in situ generated iodide) to the amine 5 can be accomplished with anexcess of the corresponding amine NHA¹A² in DMA at RT or as describedabove (step 1).

Optionally compounds 5 in which V is —CH₂— or —CH═CH— can be obtained byhydrogenation of compound 5 itself or the intermediates 9a, 9b, 9c or10. The hydrogenation may be done in EtOH with Pt₂O.H₂O (yields thesaturated analogues 5, 9a, 9b, 9c or 10) or by selective hydrogenationto the double bond with other known methods and transforming theintermediates afterwards to 5.

For the introduction of the group A¹A²N(A³A⁴C)[CH₂]_(m) in compound 8 toobtain the final compound 5 in which A³ and/or A⁴ are not H, thefollowing steps have to be performed (step m or step i and l): for m>0,the building block A¹A²N(A³A⁴C) [CH₂]_(m)-halogenide/mesylate issynthesised by known methods (or in analogy to the methods described inScheme 3) and introduced (step m) under the same condition as describedabove for step i. For m=0, the introduction of the group A¹A²N(A³A⁴C)with A³ and/or A⁴ not H, a two step procedure has to be followed: firstthe rearrangement of 8 with n-BuLi (ca 1.6 M in hexane) in THF at −78°C., followed by reaction with the corresponding aldehyde (A³ or A⁴-COH)or ketone (A³COA⁴, at −78° C. to RT) leads to the A³A⁴ substitutedpropargyl alcohol 9a (step i) which is mesylated and reacted with thedesired A¹A²-substituted-amine to yield A³A⁴-substituted compound 5(step 1).

If A²=H, heteroaromatic moieties A² may be introduced by treatment withhalo heteroaromatics in the presence of Huenig's base in DMF (Ger.Offen. (1990), DE3905364 A1). Alternatively, Buchwald conditions e.g.Pd(OAc)₂, 2-(Dicyclohexylphosphino) biphenyl, NaOtBu in toluene might beapplied (John P. Wolfe, Hiroshi Tomori, Joseph P. Sadighi, Jingjun Yin,and Stephen L. Buchwald, J. Org. Chem., 65 (4), 1158-1174, 2000).

Amine 5 can further be transformed. For Q=methyl as described in Scheme4 to the corresponding compound 5 in which Q stands for CH₂CH₂—R⁷ orCH₂CH(OH)—R⁷.

For an amine 5 in which Q is a halo-substituted aromatic system, thecorresponding alkyne, alkyl, alkene, amine, alkoxy or thioalkoxysubstituted derivative can be synthesized employing Sonogashira reactionor palladium catalyzed amination, C—O or C—S coupling reactions (asdescribed for compound 3 in scheme 4) (or in case of a hydroxysubstitution, the corresponding triflate may be synthesized).

Amine 5 may be converted to a salt or to the N-oxide 6 using a mixtureof hydrogen peroxide urea adduct and phthalic anhydride in CH₂Cl₂ at RT(step e).

Scheme 6:

Another approach for the introduction of the substituted side chain isdepicted in scheme 6. It starts by alkylation of the phenol 1 (V═O, S,n=0) directly with a suitable co-halo-alkane carboxylic ester or via thein situ generated triflate of an co-hydroxy alkane carboxylic ester inanalogy to Belostotskii, Anatoly M.; Hassner, Alfred. Synthetic methods.41. Etherification of hydroxysteroids via triflates. Tetrahedron Lett.(1994), 35(28), 5075-6(step a). For the preparation of derivatives 2(V═O, n>0), the alcohol 1 can be treated with ω-haloalkane carboxylicester (halogen is here represented by bromine, but can also be chlorineor iodine. It is also possible to use mesylates or tosylates ortriflates instead of halogenides) under phase transfer conditions. ForV═S, O or NR²—PG, the derivative 1 may be treated with ω-haloalkanecarboxylic ester in the presence of NaH in DMF 0° C. to RT to yieldester 2. Alternatively, the ester 2 can be prepared from the bromide 3(synthesis according to scheme 4) by treatment with e.g.acetocyanhydrine in acetonitrile, followed by a Pinner reaction andhydrolysis of the imidate to the corresponding ester (step b).

For V═CH═CH, the ester 2 or its corresponding acid may be prepared fromaldehyde 4 (synthesis described in scheme 5) by treatment with thecorresponding Wittig reagent X⁻Ph₃P⁺(CH₂)_(m+1)CO₂R/H. For V═C,hydrogenation of the Wittig product under standard conditions yields thesaturated product 2.

For V═C≡C, ester 2 or amide 6 may be derived from the dibromo derivative5 (synthesis according to scheme 5) by rearrangement with n-BuLi (ca 1.6M in hexane) in THF at −78 C, followed by reaction with chloroformate ordimethylcarbamoyl chloride (−78° C. to RT; step d). For longer sidechains, the rearrangement of dibromoalkene 5 may be performed withn-BuLi (ca 1.6 M in hexane) in THF at −78° C. as above, followed byaddition of a cosolvent such as DMPU and reaction with a suitableprotected 1-bromo-alkylalcohol Br—(CH₂)_(m)CH₂OH, followed by oxidationto yield the compound 2 as acid (step e).

Saponification of the ester 2 using standard conditions e.g. LiOH inEtOH, MeOH or THF, followed by treatment with NHA¹A², EDCI, HOBT and abase such as Huenig's base, NEt₃, NMM in CH₂Cl₂, DMF, DMA or dioxanegives amide 6. Amide 6 can be transferred to amine 7 (A³,A⁴=Me) byreaction with methylmagnesium bromide, ZrCl₄ in THF at low temperature(see Stephen M. Denton, Anthony Wood, A Modified Bouveault Reaction forthe Preparation of α,α-dimethylamines from Amides, Synlett 1999, 1,55-56.) or by treatment with other grignard reagents in the presence ofZrCl₄ or Ti(OiPr)₄ (see V. Chalinski, A. de Meijere, A versatile NewPreparation of Cyclopropylamines from acid dialkylamides, Angew. Chem.Int. Ed. Engl. 1996, 35, No 4, 413-4.).

For A¹=Me, A^(2′)=OMe, the amide 3 can be treated with a grignardreagent A³MgX to give the corresponding ketone 8. Reductive alkylationof the ketone 8 by treatment with NHA¹A² in the presence oftetraisopropyl orthotitanate, followed by reduction with NaCNBH₃ inethanol yields the amine 7 (see: R. J. Mattson, K. M. Pham, D. J. Leuck,K. A. Cowen, J. O. C. 1990, 55, 2552-4.).

Amine 7 may be converted to a salt or to the N-oxide 9 using a mixtureof hydrogen peroxide urea adduct and phthalic anhydride in CH₂Cl₂ at RT.

Amine 7 can be transformed further. For Q=methyl as described in Scheme4 to the corresponding compound 7 in which Q stands for CH₂CH₂—R⁷ orCH₂CH(OH)—R⁷.

For an amine 7 in which Q is a halo-substituted aromatic system, thecorresponding alkyne, alkyl, alkene, amine, alkoxy or thioalkoxysubstituted derivative can be synthesized employing Sonogashira reactionor palladium catalyzed amination, C—O or C—S coupling reactions (asdescribed for compound 3 in scheme 4) (or in case of a hydroxysubstitution, the corresponding triflate may be synthesized).

The following tests were carried out in order to determine the activityof the compounds of formula I and their salts.

Inhibition of Human Liver Microsomal 2,3-oxidosqualene-lanosterolCyclase (OSC)

Liver microsomes from a healthy volunteer were prepared in sodiumphosphate buffer (pH 7.4). The OSC activity was measured in the samebuffer, which also contained 1 mM EDTA and 1 mM dithiothreitol. Themicrosomes were diluted to 0.8 mg/ml protein in cold phosphate buffer.Dry [¹⁴C]R,S-monooxidosqualene (MOS, 12.8 mCi/mmol) was diluted to 20nCi/μl with ethanol and mixed with phosphate buffer-1% BSA (bovine serumalbumin). A stock solution of 1 mM test substance in DMSO was diluted tothe desired concentration with phosphate buffer-1% BSA. 40 μL ofmicrosomes were mixed with 20 μl of the solution of the test substanceand the reaction was subsequently started with 20 μl of the [¹⁴C]R,S-MOSsolution. The final conditions were: 0.4 mg/ml of microsomal proteinsand 30 μl of [¹⁴C]R,S-MOS in phosphate buffer, pH 7.4, containing 0.5%albumin, DMSO <0.1% and ethanol <2%, in a total volume of 80 μl.

After 1 hour at 37° C. the reaction was stopped by the addition of 0.6ml of 10% KOH-methanol, 0.7 ml of water and 0.1 ml of hexane:ether (1:1,v/v) which contained 25 μg of non-radioactive MOS and 25 μg oflanosterol as carriers. After shaking, 1 ml of hexane:ether (1:1, v/v)was added to each test tube, these were again shaken and thencentrifuged. The upper phase was transferred into a glass test tube, thelower phase was again extracted with hexane:ether and combined with thefirst extract. The entire extract was evaporated to dryness withnitrogen, the residue was suspended in 50 μl of hexane:ether and appliedto a silica gel plate. Chromatographic separation was effected inhexane:ether (1:1, v/v) as the eluent. The Rf values for the MOSsubstrate and the lanosterol product were 0.91 and, respectively, 0.54.After drying, radioactive MOS and lanosterol were observed on the silicagel plate. The ratio of MOS to lanosterol was determined from theradioactive bands in order to determine the yield of the reaction andOSC inhibition.

The test was carried out on the one hand with a constant test substanceconcentration of 100 nM and the percentage OSC inhibition againstcontrols was calculated. The more preferred compounds of the presentinvention exhibit inhibitions larger than 50%. In addition, the test wascarried out with different test substance concentrations andsubsequently the IC₅₀ value was calculated, i.e. the concentrationrequired to reduce the conversion of MOS into lanosterol to 50% of thecontrol value. The preferred compounds of the present invention exhibitIC₅₀ values of 1 nM to 10 μM, preferably of 1-100 nM.

The compounds of formula I and their pharmaceutically acceptable acidaddition salts can be used as medicaments, e.g. in the form ofpharmaceutical preparations for enteral, parenteral or topicaladministration. They can be administered, for example, perorally, e.g.in the form of tablets, coated tablets, dragees, hard and soft gelatinecapsules, solutions, emulsions or suspensions, rectally, e.g. in theform of suppositories, parenterally, e.g. in the form of injectionsolutions or infusion solutions, or topically, e.g. in the form ofointments, creams or oils.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and their pharmaceuticallyacceptable acid addition salts, optionally in combination with othertherapeutically valuable substances, into a galenical administrationform together with suitable, non-toxic, inert, therapeuticallycompatible solid or liquid carrier materials and, if desired, usualpharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragees and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers are,however, required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavour-improving agents, salts forvarying the osmotic pressure, buffer substances, solubilizers, colorantsand masking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 mg to about 1000 mg,especially about 50 mg to about 500 mg, comes into consideration for theprevention and control of topical and systemic infections by pathogenicfungi. For cholesterol lowering and treatment of impaired glucosetolerance and diabetes the daily dosage conveniently amounts to between1 and 1000 mg, preferably 5 to 200 mg, for adult patients. Depending onthe dosage it is convenient to administer the daily dosage in severaldosage units.

The pharmaceutical preparations conveniently contain about 1-500 mg,preferably 5-200 mg, of a compound of formula I.

The following Examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES

Abbreviations:

AcOH=acetic acid, Aq=aqueous, BOC=t-butyloxycarbonyl,CH₂Cl₂=dichloromethane, DAST=Diethylaminosulfur trifluoride,EDCI=N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride,Et₃N=triethylamine, Et₂O=diethylether, EtOAc=ethylacetate, EtOH=ethanol,eq=equivalents, HOBT=1-Hydroxybenzo-triazole, Huenigs base=iPr₂NEtN-ethyldiisopropylamine, LAH=Lithium aluminium hydride, LiBH₄=lithiumborohydride, MeOH=methanol, NMM=N-methyl-morpholine,TBDMSCl=t-butyldimethylsilyl chloride,Pd(Ph₃P)₄=tetrakis(triphenylphosphine)palladium,PdCl₂(PPh₃)₂=bis(triphenylphosphine)palladium(II) chloride,TFA=trifluoroacetic acid, DMAP=4-Dimethylaminopyridine,THF=tetrahydrofurane.

General Remarks

All reactions were performed under argon.

The purification of the final amines by preparative HPLC [e.g. RP-18,acetonitrile (0.1% HCOOH)/water (0.1% HCOOH), 10% to 95% acetonitrile]yielded mixtures of the corresponding amino formate and thecorresponding halogenide or mesylate which was used in the reaction. Theratio was not always determined, the purity of the final amino saltswas >80% after LC-MS.

Example 1

1.1

1.4 l of nitrobenzene were cooled in an ice bath and treated insuccession at a maximum temperature of 6° C. with 492.6 g (3.656 mol) ofaluminum chloride and 700 g (3.355 mol) of4-trifluoromethyl-2-fluoro-benzoyl chloride in 350 ml of nitrobenzene.The mixture was stirred (15 min) and 427.5 g (3.388 mol) of3-fluoroanisole were added slowly so that the temperature did not riseabove 6° C. The solution was left to warm to room temperature, stirred 2h at this temperature, poured on to ice-water (2.5 l) and extracted withmethylene chloride. The organic phase was washed with water andconcentrated. After crystallization from THF (1.2l)/hexane (4.2l), 237 g(24%) of(2-Fluoro-4-methoxy-phenyl)-(4-trifluoromethyl-phenyl)-methanone wereobtained, MS: 298 (M).

1.2

12.01 g (107 mmol) of potassium tert. butylate were dissolved in 425 mlof THF and treated slowly with 13.29 g (107 mmol) of benzyl mercaptane.The suspension was stirred at RT (1 h) and then treated with 29.56 g (99mmol) of(2-Fluoro-4-methoxy-phenyl)-(4-trifluoromethyl-phenyl)-methanone in 220ml of THF. The solution was stirred at RT (2 h), evaporated and treatedwith EtOAc/aqueous NaHCO₃ solution and dried (Na₂SO₄). 42.8 g(corresponds to 99 mmol) of(2-Benzylsulfanyl-4-methoxy-phenyl)-(4-trifluoromethyl-phenyl)-methanonewere obtained which were taken up in 340 ml of methylene chloride,treated at 0° C. with 13.38 g (99 mmol) of sulphuryl chloride andstirred at 0° C. for 90 min. After evaporation, the residue was taken upin 307 ml of THF, treated at 0° C. with 307 ml of a saturated ammoniasolution in ethanol and stirred (16 h at RT). The solvent was removedand the residue was again taken up in sodium hydrogen carbonate solutionand ethyl acetate. The phases were separated and the inorganic phase wasextracted with ethyl acetate. The organic phases were washed with sodiumchloride solution and dried. Recrystallization from CH₂Cl₂/methanol(−20° C.) yielded 19.8 g (71%) of6-Methoxy-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole, MS: 309 (M).

1.3

A solution of 20 g (64.66 mmol) of6-Methoxy-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole in 150 ml ofacetic acid and 75 ml 62% aqueous HBr solution was heated to reflux for70 h, subsequently cooled and taken up in ice water and extracted withtert-butylmethyleter (3×). The organic phases were washed with saturatedsodium hydrogen carbonate solution (3×) and dried (Na₂SO₄). The residuewas suspended in 350 ml boiling CH₂Cl₂, cooled to 3° C. and filtered toyield 15.8 g (83%) of3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-ol, MS: 295 (M).

1.4

In analogy to examples 1.1 to 1.3, 4-bromo-benzoyl chloride and3-fluoroanisole were converted to yield3-(4-bromo-phenyl)-benzo[d]isothiazol-6-ol, MS: 305 (M, 1Br).

1.5

In analogy to examples 1.1 to 1.3, 4-chloro-benzoyl chloride and3-fluoroanisole were converted to yield3-(4-chloro-phenyl)-benzo[d]isothiazol-6-ol, MS: 261 (M, 1Cl).

1.6

In analogy to examples 1.1 to 1.3, 4-fluoro-benzoyl chloride and3-fluoroanisole were converted to yield3-(4-Fluoro-phenyl)-benzo[d]isothiazol-6-ol as white solid, MS: 245 (M).

1.7

In analogy to example 1.2 to 1.3, 2-fluoro-4-methoxyacetophenone gave3-Methyl-benzo[d]isothiazol-6-ol, MS: 166 (MH⁺).

Example 2

2.1

2.0 g (6.55 mmol) 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-ol in 30 mlacetone were treated with 5.89 g (42.5 mmol, 6.5 eq) K₂CO₃ and 1.9 ml(16.33 mmol, 2.5 eq) 1,4-dibromobutane. The reaction mixture was stirredat 45° C. for 8 h and at RT over night, filtered and evaporated. Theexcess of dibromide was removed in vacuo and the crude product waspurified by column chromatography on silica gel with a gradientEtOAc:hexane 1:9 to 1:4 to yield 2.0 g (71%)6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole as yellowsemisolid, MS: 439 (M, 2Br).

2.2

In analogy to example 2.1, 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-oland 1,2-dibromoethane were converted to yield6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole as off-whitesolid, 105° C., MS: 411 (M, 2Br).

2.3

In analogy to example 2.1, 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-oland 1,3-dibromopropane were converted to yield3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole as yellowoil, MS: 425 (M, 2Br).

2.4

In analogy to example 2.1,3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-ol and1,4-dibromobutane were converted to yield6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole aslight yellow solid, MS: 429 (M, 1Br).

2.5

In analogy to example 2.1, 3-(4-chloro-phenyl)-benzo[d]isothiazol-6-oland 1,4-dibromobutane were converted to yield6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole as whitesolid, mp: 68-69° C., MS: 395 (M, 1Br, 1 Cl).

2.6

In analogy to example 2.1, 3-(4-fluoro-phenyl)-benzo[d]isothiazol-6-oland 1,4-dibromobutane were converted to yield6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[d]isothiazole, MS: 379 (M,1Br).

2.7

In analogy to example 2.1, 3-Methyl-benzo[d]isothiazol-6-ol and1,3-dibromobutane were converted to yield6-(4-Bromo-butoxy)-3-methyl-benzo[d]isothiazole as brown oil, MS: 300(MH⁺, 1 Br).

Example 3

3.1

75 mg (0.18 mmol)6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole in 2.5 ml DMAwere treated with 98 μl (0.54 mmol, 3 eq) 5.6 M N,N-dimethylamine inethanol for 35 h at RT. The solution was diluted with ether and asaturated aqueous solution of NaHCO₃. The inorganic phase was extractedwith ether, the combined organic phases were washed with brine and driedover Na₂SO₄. Column chromatography on silica gel with CH₂Cl₂:MeOH 8:1yielded 63 mg (92%)[2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethyl]-dimethyl-amineas colorless oil, MS: 377(MH⁺, 1Br).

3.2

In analogy to example 3.1,6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole andN-Allylmethylamine were converted to yieldAllyl-[2-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethyl]-methyl-amineas colorless oil, MS: 403(MH⁺, 1Br).

3.3

In analogy to example 3.1,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole andN-Allylmethylamine were converted to yieldAllyl-[3-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-methyl-amineas colorless oil, MS: 417(MH⁺, 1Br).

3.4

In analogy to example 3.1,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole andDimethylamine were converted to yield[3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-dimethyl-amineas white semisolid, MS: 391(MH⁺, 1Br).

3.5

In analogy to example 3.1,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole andN-(2-methoxyethyl)ethylamine were converted to yield (withoutextraction)[3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-ethyl-(2-methoxy-ethyl)-aminehydrobromide as colorless oil, MS: 449(MH⁺, 1Br).

3.6

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole andN-Allylmethylamine were converted to yieldAllyl-[4-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-methyl-amineas white semisolid, MS: 431(MH⁺, 1Br).

3.7

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole andDimethylamine were converted to yield[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-dimethyl-amineas white semisolid, MS: 405(MH⁺, 1Br).

3.8

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole andN-(2-Methoxyethyl)ethylamine were converted to{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-aminewhich was converted to the hydrochloride by treatment with HCl inmethanol to yield{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-aminehydrochloride as light yellow oil, MS: 463(MH⁺, 1Br).

3.9

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and piperidinewere converted to yield3-(4-Bromo-phenyl)-6-(4-piperidin-1-yl-butoxy)-benzo[d]isothiazole aswhite solid, MS: 445(MH⁺, 1Br).

3.10

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and1-Methylpiperazine were converted to yield3-(4-Bromo-phenyl)-6-[4-(4-methyl-piperazin-1-yl)-butoxy]-benzo[d]isothiazoleas white solid, MS: 460(MH⁺, 1Br).

3.11

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and1-Acetylpiperazine were converted to yield1-(4-(4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl)-piperazin-1-yl)-ethanoneas white solid, MS: 488(MH⁺, 1Br).

3.12

In analogy to example 3.1,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole andHydroxyethylamine were converted to yield2-{3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propylamino}-ethanolas white semisolid, MS: 407 (MH⁺, 1Br).

3.13

In analogy to example 3.1,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole andMethyl-prop-2-ynyl-amine were converted to yield{3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-methyl-prop-2-ynyl-amineas colorless oil, MS: 415 (MH⁺, 1Br).

3.14

In analogy to example 3.1,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole andProp-2-ynylamine were converted to yield{3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-prop-2-ynyl-amineas off-white semisolid, MS: 401 (MH⁺, 1Br).

3.15

In analogy to example 3.1,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole andPiperidine were converted to yield3-(4-Bromo-phenyl)-6-(3-piperidin-1-yl-propoxy)-benzo[d]isothiazole aspink oil, MS: 431 (MH⁺, 1Br).

3.16

In analogy to example 3.1,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and1-Methyl-piperazine were converted to yield3-(4-Bromo-phenyl)-6-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzo[d]isothiazoleas colorless oil, MS: 446 (MH⁺, 1Br).

3.17

In analogy to example 3.1,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and1-piperazin-1-yl-ethanone were converted to yield1-(4-{3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-piperazin-1-yl)-ethanoneas colorless oil, MS: 474 (MH⁺, 1Br).

3.18

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and Ethylaminewere converted to yield{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amine aswhite solid, MS: 405 (MH⁺, 1Br).

3.19

In analogy to example 3.1,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole andEthylamine were converted to yield{3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-ethyl-amineas white solid, MS: 391 (MH⁺, 1Br).

3.20

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[d]isothiazole andmethylaminoethanol were converted to yield2-({4-[3-(4-Fluoro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-amino)-ethanolwhich was transferred into its salt by treatment with formic acid, MS:375 (MH⁺).

3.21

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[d]isothiazole andN-(2-Methoxyethyl)methylamine were converted to yield{4-[3-(4-Fluoro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-aminewhich was transferred into its salt by treatment with formic acid, MS:389 (MH⁺).

3.22

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[d]isothiazole andN-(2-Methoxyethyl)ethylamine were converted to yieldEthyl-{4-[3-(4-fluoro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-aminewhich was transferred into its salt by treatment with formic acid, MS:403 (MH⁺).

3.23

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[d]isothiazole andethylaminoethanol were converted to yield2-(Ethyl-{4-[3-(4-fluoro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanolwhich was transferred into its salt by treatment with formic acid, MS:389 (MH⁺).

3.24

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-methyl-benzo[d]isothiazole Ethylaminoethanol wereconverted to yield2-{Ethyl-[4-(3-methyl-benzo[d]isothiazol-6-yloxy)-butyl]-amino}-ethanolas yellow oil, MS: 309 (MH⁺).

3.25

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-methyl-benzo[d]isothiazoleN-(2-Methoxyethyl)ethylamine were converted to yieldEthyl-(2-methoxy-ethyl)-[4-(3-methyl-benzo[d]isothiazol-6-yloxy)-butyl]-amineas yellow oil, MS: 323 (MH⁺).

Example 4

1 eq of the corresponding bromide was treated with 3 eq of thecorresponding amine in DMF (1 ml/mmol bromide) in the presence of 1 eqdiisopropylethylamine and a catalytic amount of NaI at RT until nostarting material could be detected with HPLC. Formic acid was added andthe crude materials were purified by preparative HPLC [RP-18,acetonitrile (0.1% HCOOH)/water (0.1% HCOOH), 10% to 95% acetonitrile].After evaporation the product was obtained as a mixture of aminohydrobromides and formates.

4.1

According to the method in example 4,6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and2-(methylamino)ethanol were converted to yield2-[[2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethyl]-methyl-amino]-ethanol,MS: 408 (MH⁺, 1Br).

4.2

According to the method in example 4,6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole andN-(2-methoxyethyl)methylamine were converted to yield[2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethyl]-(2-methoxy-ethyl)-methyl-amine,MS: 422 (MH⁺, 1Br).

4.3

According to the method in example 4,6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and morpholinewere converted to yield3-(4-Bromo-phenyl)-6-(2-morpholin-4-yl-ethoxy)-benzo[d]isothiazole, MS:420 (MH⁺, 1Br).

4.4

According to the method in example 4,6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and2-(ethylamino)ethanol were converted to yield2-[[2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethyl]-ethyl-amino]-ethanol,MS: 422 (MH⁺, 1Br).

4.5

According to the method in example 4,6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole andpyrrolidine were converted to yield3-(4-Bromo-phenyl)-6-(2-pyrrolidin-1-yl-ethoxy)-benzo[d]isothiazole, MS:404 (MH⁺, 1Br).

4.6

According to the method in example 4,6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and azetidinewere converted to yield6-(2-Azetidin-1-yl-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole, MS:390 (MH⁺, 1Br).

4.7

According to the method in example 4,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and2-(methylamino)ethanol were converted to yield2-[[3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-methyl-amino]-ethanol,MS: 422 (MH⁺, 1Br).

4.8

According to the method in example 4,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole andN-(2-methoxyethyl)methylamine were converted to yield[3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-(2-methoxy-ethyl)-methyl-amine,MS: 436 (MH⁺, 1Br).

4.9

According to the method in example 4,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole andmorpholine were converted to yield3-(4-Bromo-phenyl)-6-(3-morpholin-4-yl-propoxy)-benzo[d]isothiazole, MS:434 (MH⁺, 1Br).

4.10

According to the method in example 4,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and2-(ethylamino)ethanol were converted to yield2-[[3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-ethyl-amino]-ethanol,MS: 436 (MH⁺, 1Br).

4.11

According to the method in example 4,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole andpyrrolidine were converted to yield3-(4-Bromo-phenyl)-6-(3-pyrrolidin-1-yl-propoxy)-benzo[d]isothiazole,MS: 418 (MH⁺, 1Br).

4.12

According to the method in example 4,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and azetidinewere converted to yield6-(3-Azetidin-1-yl-propoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole, MS:404 (MH⁺, 1Br).

4.13

According to the method in example 4,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and2-(methylamino)ethanol were converted to yield2-[[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-methyl-amino]-ethanol,MS: 436 (MH⁺, 1Br).

4.14

According to the method in example 4,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole andN-(2-methoxyethyl)methylamine were converted to yield[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-(2-methoxy-ethyl)-methyl-amine,MS: 450 (MH⁺, 1Br).

4.15

According to the method in example 4,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and morpholinewere converted to yield3-(4-Bromo-phenyl)-6-(4-morpholin-4-yl-butoxy)-benzo[d]isothiazole, MS:448 (MH⁺, 1Br).

4.16

According to the method in example 4,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and2-(ethylamino)ethanol were converted to yield2-[[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-ethyl-amino]-ethanol,MS: 450 (MH⁺, 1Br).

4.17

According to the method in example 4,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole andpyrrolidine were converted to yield3-(4-Bromo-phenyl)-6-(4-pyrrolidin-1-yl-butoxy)-benzo[d]isothiazole, MS:432 (MH⁺, 1Br).

4.18

According to the method in example 4,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and azetidinewere converted to yield6-(4-Azetidin-1-yl-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole, MS:418 (MH⁺, 1Br).

Example 5

1 eq of the corresponding bromide was treated with 3 eq of thecorresponding amine in DMA (1 ml/0.25 mmol bromide) at RT until nostarting material could be detected with HPLC. Formic acid was added andthe crude materials were purified by preparative HPLC [RP-18,acetonitrile (0.1% HCOOH)/water (0.1% HCOOH), 10% to 95% acetonitrile].After evaporation the product was obtained as a mixture of aminohydrobromides and formates.

5.1

According to the method in example 5,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole anddiethanolamine were converted to yield2-[[3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-(2-hydroxy-ethyl)-amino]-ethanolas white semisolid, MS: 451 (MH⁺, 1Br).

5.2

According to the method in example 5,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole andbis(2-methoxyethyl)amine were converted to yield[3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-bis-(2-methoxy-ethyl)-amineas orange oil, MS: 479 (MH⁺, 1Br).

5.3

According to the method in example 5,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole anddiethanolamine were converted to yield2-[[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-(2-hydroxy-ethyl)-amino]-ethanolas white semisolid, MS: 465(MH⁺, 1Br).

5.4

According to the method in example 5,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole andbis(2-methoxyethyl)amine were converted to yield[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-bis-(2-methoxy-ethyl)-amineas light yellow oil, MS: 493 (MH⁺, 1Br).

Example 6

1 eq of the corresponding bromide was treated with 3 eq of thecorresponding amine in DMA (1 ml/0.25 mmol bromide) at RT until nostarting material could be detected with HPLC. Formic acid was added andthe crude materials were purified by prep HPLC [RP-18, acetonitrile(0.1% HCOOH)/water (0.1% HCOOH), 10% to 95% acetonitrile]. Afterseparation, the product was extracted with EtOAc and sat. NaHCO₃/H₂O toisolate the product as free amine. The hydrochloride salt was optionallyobtained after addition of 1N HCl/MeOH and evaporation of the solvent.

6.1

According to the method in example 6,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and1,1-dimethylpropargylamine were converted to yield{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-(1,1-dimethyl-prop-2-ynyl)-amineas colorless oil, MS: 443(MH⁺, 1Br).

6.2

According to the method in example 6,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole andethanolamine were converted to yield2-{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butylamino}-ethanolas white solid, MS: 421(MH⁺, 1Br).

6.3

According to the method in example 6,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole andMethyl-prop-2-ynyl-amine were converted to yield{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-prop-2-ynyl-amineas light yellow oil, MS: 429(MH⁺, 1Br).

6.4

According to the method in example 6,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole andpropargylamine were converted to yield{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-prop-2-ynyl-aminehydrochloride as off-white solid, MS: 415(MH⁺, 1Br).

Example 7

A solution of 0.25 mmol (1 equivalent) of the corresponding bromide in0.7 ml dry DMA was treated with a solution of 0.5 mmol (2 equivalents)of the corresponding secondary amine in 0.15 ml dry DMA at roomtemperature. After 16 h, 2 equivalents of secondary amine were addedagain to the solution. The reaction mixture was allowed to stand overnight at room temperature, treated with 0.2 ml formic acid and purifiedby preparative HPLC [RP-18, acetonitrile (0.1% HCOOH)/water (0.1%HCOOH), 10% to 95% acetonitrile]. After evaporation, the product wasobtained as a mixture of amino hydrobromide and formate. Optionally theproduct was extracted with EtOAc and sat. NaHCO₃/H₂O to obtain thecorresponding free amine.

7.1

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole andDiethylamine were converted to yieldDiethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amine,MS: 423 (MH⁺).

7.2

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole andPiperidine were converted to yield6-(4-Piperidin-1-yl-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole,MS: 435 (MH⁺).

7.3

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole andAllylmethylamine were converted to yieldAllyl-methyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amine,MS: 421 (MH⁺).

7.4

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole andTrimethylene imine were converted to yield6-(4-Azetidin-1-yl-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole,MS: 407 (MH⁺).

7.5

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole andEthylamino ethanol were converted to yield2-(Ethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanol,MS: 439 (MH⁺).

7.6

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole andDiethanoleamine were converted to yield2-((2-Hydroxy-ethyl)-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanol,MS: 455 (MH⁺).

7.7

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole andDimethylamine were converted to yieldDimethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amine,MS: 395 (MH⁺).

7.8

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole andN-Allylmethylamine were converted to yieldAllyl-{4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-amine,MS: 387 (MH⁺, 1Cl).

7.9

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and2-Ethylamino-ethanol were converted to yield2-({4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanol,MS: 405 (MH⁺, 1Cl).

7.10

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and Azetidinewere converted to yield6-(4-Azetidin-1-yl-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole, MS:373 (MH⁺, 1Cl).

7.11

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole andPiperidine were converted to yield3-(4-Chloro-phenyl)-6-(4-piperidin-1-yl-butoxy)-benzo[d]isothiazole, MS:401 (MH⁺, 1Cl).

7.12

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole andN-(2-Methoxyethyl)ethylamine were converted to yield{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine,MS: 419 (MH⁺, 1Cl).

7.13

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole andDiethylamine were converted to yield{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-diethyl-amine,MS: 389 (MH⁺, 1Cl).

7.14

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole andN-Methylcyclopropanemethylamine were converted to yield{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-cyclopropylmethyl-methyl-amine,MS: 401 (MH⁺, 1Cl).

7.15

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole andN-Isopropylmethylamine were converted to yield{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-isopropyl-methyl-amine,MS: 389 (MH⁺, 1Cl).

7.16

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole andPyrrolidine were converted to yield3-(4-Chloro-phenyl)-6-(4-pyrrolidin-1-yl-butoxy)-benzo[d]isothiazole,MS: 387 (MH⁺, 1Cl).

7.17

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole andN-(2-Methoxyethyl)Methylamine were converted to yield{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine,MS: 405 (MH⁺, 1Cl).

7.18

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and2-(Methylamino)Ethanol were converted to yield2-({4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-amino)-ethanol,MS: 391 (MH⁺, 1Cl).

7.19

According to the method in example 7,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and(R)-3-Hydroxypyrrolidine were converted to yield(3R)-1-{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-pyrrolidin-3-ol,MS: 403 (MH⁺, 1Cl).

Example 8

8.1

To 4.4 g (10 mmol)6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole in 400 mlCH₂Cl₂, 24 g potassium permanganate on silica gel were added, which wereprepared from 7 g KMnO₄, 20 g silica gel and 10 ml water prior to use.The mixture was stirred at 50° C. for 2 days, filtered and the crudematerial purified by column chromatography with EtOAc:hexane 1:4 to give1.6 g (34%) 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole1,1-dioxide as off-white solid, MS: 473 (MH⁺, 1Br).

8.2

In analogy to example 8.1,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole was convertedto 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole1,1-dioxide as off-white solid, MS: 457 (M, 2Br).

8.3

In analogy to example 8.1,6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole wasconverted to6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole1,1-dioxide as light brown solid, which was used in subsequent reactionsteps without further purification.

8.4

In analogy to example 8.1,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole was convertedto 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole1,1-dioxide as light yellow solid, MS: 426 (M, 1Br, 1Cl).

Example 9

1 eq of the corresponding bromide was treated with 3 eq of thecorresponding amine in DMA (1 ml/0.25 mmol bromide) at RT until nostarting material could be detected with HPLC. Formic acid was added andthe crude materials were purified by preparative HPLC [RP-18,acetonitrile (0.1% HCOOH)/water (0.1% HCOOH), 10% to 95% acetonitrile].After evaporation the product was obtained as a mixture ofamino-hydrobromides and formates.

9.1

According to the method in example 9,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole 1,1-dioxideand dimethylamine were converted to yield(3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-propyl)-dimethyl-amine as yellow solid,MS: 423 (MH⁺, 1Br).

9.2

According to the method in example 9,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole 1,1-dioxideand N-allylmethylamine were converted to yieldAllyl-(3-[3-(4-bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-propyl)-methyl-amine as yellow solid, MS:449 (MH⁺, 1Br).

9.3

According to the method in example 9,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole 1,1-dioxideand azetidine were converted to yield6-(3-Azetidin-1-yl-propoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole1,1-dioxide as yellow solid, MS: 435 (MH⁺, 1Br).

9.4

According to the method in example 9,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole 1,1-dioxideand N-Methylproylamine were converted to yield{3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-propyl}-methyl-propyl-amine as yellowsolid, MS: 451 (MH⁺, 1Br).

9.5

According to the method in example 9,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole 1,1-dioxideand 2-Ethylaminoethanol were converted to yield2-({3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-propyl}-ethyl-amino)-ethanol as yellowsolid, MS: 467(MH⁺, 1Br).

9.6

According to the method in example 9,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole 1,1-dioxideand diethylamine were converted to yield{3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-propyl}-diethyl-amine as yellow solid, MS:451 (MH⁺, 1Br).

9.7

According to the method in example 9,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole 1,1-dioxideand N-(2-methoxyethyl)methylamine were converted to yield{3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-propyl}-(2-methoxy-ethyl)-methyl-amine asyellow solid, MS: 467 (MH⁺, 1Br).

9.8

According to the method in example 9,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole 1,1-dioxideand 2-methylaminoethanol were converted to yield2-({3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-propyl}-methyl-amino)-ethanol as yellowsolid, MS: 453 (MH⁺, 1Br).

9.9

According to the method in example 9,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole 1,1-dioxideand N-(2-methoxyethyl)ethylamine were converted to yield{3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-propyl}-ethyl-(2-methoxy-ethyl)-amine asyellow solid, MS: 481 (MH⁺, 1Br).

9.10

According to the method in example 9,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole 1,1-dioxideand dimethylamine were converted to yield(4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl)-dimethyl-amine as yellow solid, MS:437 (MH⁺, 1Br).

9.11

According to the method in example 9,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole 1,1-dioxideand N-allylmethylamine were converted to yieldAllyl-(4-[3-(4-bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl)-methyl-amine as yellow solid, MS:463 (MH⁺, 1Br).

9.12

According to the method in example 9,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole 1,1-dioxideand azetidine were converted to yield6-(4-Azetidin-1-yl-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole1,1-dioxide as yellow solid, MS: 449 (MH⁺, 1Br).

9.13

According to the method in example 9,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole 1,1-dioxideand N-Methylproylamine were converted to yield{4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-propyl-amine as yellowsolid, MS: 465 (MH⁺, 1Br).

9.14

According to the method in example 9,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole 1,1-dioxideand 2-Ethylaminoethanol were converted to yield2-({4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanol as yellowsolid, MS: 481 (MH⁺, 1Br).

9.15

According to the method in example 9,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole 1,1-dioxideand diethylamine were converted to yield{4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-diethyl-amine as yellow solid, MS:465 (MH⁺, 1Br).

9.16

According to the method in example 9,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole 1,1-dioxideand N-(2-methoxyethyl)methylamine were converted to yield{4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine asyellow solid, MS: 481 (MH⁺, 1Br).

9.17

According to the method in example 9,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole 1,1-dioxideand 2-methylaminoethanol were converted to yield2-({4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-amino)-ethanol as yellowsolid, MS: 467 (MH⁺, 1Br).

9.18

According to the method in example 9,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole 1,1-dioxideand N-(2-methoxyethyl)ethylamine were converted to yield{4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine asyellow solid, MS: 495 (MH⁺, 1Br).

9.19

According to the method in example 9,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole 1,1-dioxideand bis(2-methoxyethyl)amine were converted to yield(4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl)-bis-(2-methoxy-ethyl)-amine, whichwas converted with HCl/MeOH to yield the corresponding hydrochloride asyellow semisolid, MS: 525(MH⁺, 1Br).

Example 10

A solution of 0.25 mmol (1 equivalent) of the corresponding bromide in0.7 ml dry DMA was treated with a solution of 0.5 mmol (2 equivalents)of the corresponding secondary amine in 0.15 ml dry DMA at roomtemperature. After 16 h, additional 2 equivalents of secondary aminewere added to the solution. The reaction mixture was allowed to standover night at room temperature, treated with 0.2 ml formic acid andpurified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH)/water(0.1% HCOOH), 10% to 95% acetonitrile]. After evaporation, the productwas obtained as a mixture of amino hydrobromide and formate.

10.1

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole1,1-dioxide and Allylmethylamine were converted to yieldAllyl-{4-[1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-amine, MS: 453 (MH⁺).

10.2

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole1,1-dioxide and 2-Ethylaminoethanol were converted to yield2-({4-[1,1-Dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanol, MS: 471(MH⁺).

10.3

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole1,1-dioxide and Diethylamine were converted to yield{4-[1,1-Dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-diethyl-amine, MS: 455 (MH⁺).

10.4

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole1,1-dioxide and Dimethylamine were converted to yield{4-[1,1-Dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-dimethyl-amine, MS: 427 (MH⁺).

10.5

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole1,1-dioxide and Piperidine were converted to yield6-(4-Piperidin-1-yl-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole1,1-dioxide, MS: 467 (MH⁺).

10.6

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole1,1-dioxide and Trimethyleneamine were converted to yield6-(4-Azetidin-1-yl-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole1,1-dioxide, MS: 439 (MH⁺).

10.7

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole1,1-dioxide and Diethanolamine were converted to yield2-[{4-[1,1-Dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol,MS: 487 (MH⁺).

10.8

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxideand Piperidine were converted to yield3-(4-Chloro-phenyl)-6-(4-piperidin-1-yl-butoxy)-benzo[d]isothiazole1,1-dioxide, MS: 433 (MH⁺, 1Cl).

10.9

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxideand Allyl-methyl-amine were converted to yieldAllyl-{4-[3-(4-chloro-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-amine, MS: 419 (MH⁺, 1Cl).

10.10

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxideand Azetidine were converted to yield6-(4-Azetidin-1-yl-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole1,1-dioxide, MS: 405 (MH⁺, 1Cl).

10.11

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxideand Ethyl-(2-methoxy-ethyl)-amine were converted to yield{4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine, MS:451 (MH⁺, 1Cl).

10.12

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxideand 2-Ethylamino-ethanol were converted to yield2-({4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanol, MS: 437 (MH⁺,1Cl).

10.13

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxideand Diethyl-amine were converted to yield{4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-diethyl-amine, MS: 421 (MH⁺, 1Cl).

10.14

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxideand 2-Methylamino-ethanol were converted to yield2-({4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-amino)-ethanol, MS: 423(MH⁺, 1Cl).

10.15

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxideand (2-Methoxy-ethyl)-methyl-amine were converted to yield{4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine, MS:437 (MH⁺, 1Cl).

10.16

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxideand Pyrrolidine were converted to yield3-(4-Chloro-phenyl)-6-(4-pyrrolidin-1-yl-butoxy)-benzo[d]isothiazole1,1-dioxide, MS: 419 (MH⁺, 1Cl).

10.17

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxideand (3R)-Pyrrolidin-3-ol were converted to yield1-{4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-pyrrolidin-3-ol, MS: 435 (MH⁺,1Cl).

10.18

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxideand Isopropyl-methyl-amine were converted to yield{4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-isopropyl-methyl-amine, MS: 421(MH⁺, 1Cl).

10.19

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxideand Cyclopropylmethyl-methyl-amine were converted to yield{4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-cyclopropylmethyl-methyl-amine, MS:433 (MH⁺, 1Cl).

10.20

According to the method in example 10,6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole 1,1-dioxideand N-Methylpropylamine were converted to yield{4-[3-(4-Chloro-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-propyl-amine, MS: 421 (MH⁺,1Cl).

Example 11

11.1

To a suspension of 36 mg (0.38 mmol, 2.2 eq) Hydrogen peroxide.Ureaadduct in 0.2 ml CH₂Cl₂, 28 mg (0.19 mmol, 1.1 eq) phthalic anhydridewere added and stirred for 15 min at RT. 75 mg (0.17 mmol, 1.0 eq){4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-dimethyl-amine in 0.3 ml CH₂Cl₂were added and the mixture was stirred at RT for 2 h. 1M aqueous K₂CO₃solution was added (pH 7) and the inorganic phase was extracted withCH₂Cl₂. The organic phases were washed with water and brine and driedover Na₂SO₄. Column chromatography on silica gel with CH₂Cl₂:MeOH 8:1yielded 48 mg (62%) {4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-dimethyl-amine N-oxide as lightyellow semisolid, MS: 453(MH⁺, 1Br).

11.2

In analogy to example 11.1, {4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine wasconverted to yield {4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amineN-oxide as light yellow semisolid, MS: 497 (MH⁺, 1Br).

11.3

In analogy to example 11.1, (4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl)-bis-(2-methoxy-ethyl)-amine wasconverted to yield (4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[d]isothiazol-6-yloxy]-butyl)-bis-(2-methoxy-ethyl)-amine N-oxideas yellow semisolid, MS: 541 (MH⁺, 1Br).

11.4

In analogy to example 11,1,{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-aminewas converted to{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amineN-oxide which was dissolved in THF and treated with 1M Bu₄NF in THF overnight (see example 36.1) to yield2-({4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanolN-oxide as off-white semisolid, MS: 465 (MH⁺, 1Br).

Example 12

12.1

5.0 g (16.33 mmol) 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-ol in 8 mlpyridine were treated with 3 ml (17.96 mmol) trifluoromethane sulfonicanhydride at 0° C. The solution was stirred for 1.5 h at RT. Thesolution was diluted with ether and water, the phases were separated andthe inorganic phase was extracted with ether. The combined organicphases were washed with 2M HCl and brine and dried over Na₂SO₄.Evaporation yielded 7.21 crude Trifluoro-methanesulfonic acid3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl ester as yellow oil, MS: 437(M, 1Br).

12.2

In analogy to example 12.1,3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-ol andtrifluoromethane sulfonic anhydride were converted to yieldTrifluoro-methanesulfonic acid3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester as lightbrown solid, MS: 427 (M).

12.3

In analogy to example 12.1, 3-(4-chloro-phenyl)-benzo[d]isothiazol-6-oland trifluoromethane sulfonic anhydride were converted to yieldTrifluoro-methanesulfonic acid3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl ester as orange oil, MS: 393(MH⁺, 1Cl).

Example 13

13.1

3.0 g (6.846 mmol) Trifluoro-methanesulfonic acid3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl ester were suspended threetimes with toluene prior to the reaction, then dissolved in 25 ml THFand added to 240 mg (0.34 mmol) PdCl₂(PPh₃)₂. To this suspension 0.67 ml(7.19 mmol) 4-pentyn-1-ol in 1 ml THF were added, followed by 54 mg(0.205 mmol) triphenylphosphine in 1 ml THF and 2.9 ml (20.54 mmol)triethylamine. The solution was stirred for 20 min at RT prior to theaddition of 13 mg (0.07 mmol) CuI. The solution was heated to 50° C.overnight. Further 132 μl (1.4 mmol) 4-pentyn-1-ol in 0.8 ml THF wereadded in two portions and stirring at 50° C. was continued for 5 h andat RT over night. The reaction mixture was diluted with EtOAc and 1MKHSO₄. The inorganic phase was extracted with EtOAc and the combinedorganic phases were washed with water and brine and dried over Na₂SO₄.Column chromatography with a gradient hexane:EtOAc 2:1 to 1:1 gave 1.83g (72%) 5-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol aslight yellow oil, MS: 371 (M, 1Br).

13.2

In analogy to example 13.1, Trifluoro-methanesulfonic acid3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl ester and 2-propyn-1-ol wereconverted to yield3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol as lightbrown solid, MS: 343 (MH⁺, 1Br).

13.3

In analogy to example 13.1, Trifluoro-methanesulfonic acid3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl ester and 3-butyn-1-ol wereconverted to yield4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol as orangesolid, MS: 357 (M, 1Br).

13.4

In analogy to example 13.1, Trifluoro-methanesulfonic acid3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl ester and2-Methyl-3-butyn-2-ol were converted to yield4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-2-methyl-but-3-yn-2-ol aslight yellow semisolid, MS: 371 (M, 1Br).

Example 14

14.1

To 3.3 g (7.72 mmol) Trifluoro-methanesulfonic acid3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester in 20 mlpiperidine 447.0 mg (3.9 mmol) tetrakis(triphenylphosphine)palladium and73.6 mg (3.9 mmol) CuI were added. At 80° C. 1.43 ml (15.45 mmol)4-pentyn-1-ol were added slowly, and the solution was stirred for anadditional hour. The cooled solution was added to ice water, acidifiedwith 2M HCl and extracted with ether. The combined organic phases werewashed with water and dried over Na₂SO₄. Column chromatography on silicagel with CH₂Cl₂:MeOH 30:1 yielded 2.7 g (96%)5-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-olas orange oil, MS: 361(M).

14.2

In analogy to example 14.1, Trifluoro-methanesulfonic acid3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and2-propyn-1-ol were converted to yield3-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-olas off-white solid, MS: 333(M).

14.3

In analogy to example 14.1, Trifluoro-methanesulfonic acid3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and3-butyn-1-ol were converted to yield4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-olas orange semisolid, MS: 347 (M).

14.4

In analogy to example 14.1, Trifluoro-methanesulfonic acid3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl ester and 2-propyn-1-ol wereconverted to yield3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol as yellowsolid, MS: 299 (M, 1 Cl).

14.5

In analogy to example 14.1, Trifluoro-methanesulfonic acid3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl ester and 3-butyn-1-ol wereconverted to yield4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol as yellowsolid, mp: 128-129° C., MS: 313 (M, 1 Cl).

14.6

In analogy to example 14.1, Trifluoro-methanesulfonic acid3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl ester and 4-pentyn-1-ol wereconverted to yield5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol as yellowoil, MS: 327 (M, 1 Cl).

Example 15

15.1

365 mg (1.02 mmol)4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol in 7 mlCH₂Cl₂ were treated with 94 μl (1.21 mmol) methane sulfonic acidchloride, 0.13 ml (1.53 mmol) pyridine and 135 mg (1.2 mmol) DMAP at 0°C. The solution was stirred at RT over night, was diluted with water andacidified with 10% aq. KHSO₄. The inorganic phase was extracted withCH₂Cl₂. The combined organic phases were washed with NaHCO₃ solution,brine and dried over Na₂SO₄. Evaporation gave 446 mg crudeMethanesulfonic acid4-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl ester, MS: 436(MH⁺).

15.2

In analogy to example 15.1,3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol andmethane sulfonyl chloride were converted to yield Methanesulfonic acid3-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester, whichwas directly subjected to the following reaction.

15.3

In analogy to example 15.1,5-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol andmethane sulfonyl chloride were converted to yield Methanesulfonic acid5-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester, MS:450 (MH⁺, 1Br).

15.4

In analogy to example 15.1,3-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-oland methane sulfonyl chloride were converted to yield Methanesulfonicacid3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynylester, which was directly subjected to the following reaction.

15.5

In analogy to example 15.1,5-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-oland methane sulfonyl chloride were converted to yield Methanesulfonicacid5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynylester light brown oil, MS: 369(M).

15.6

In analogy to example 15.1,3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol andmethane sulfonyl chloride were converted to yield Methanesulfonic acid3-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester as abrown oil, MS: 377 (M, 1Cl).

15.7

In analogy to example 15.1,4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol andmethane sulfonyl chloride were converted to yield Methanesulfonic acid4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl ester as alight yellow oil, MS: 391 (M, 1Cl).

15.8

In analogy to example 15.1,5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol andmethane sulfonyl chloride were converted to yield Methanesulfonic acid5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester as alight yellow oil, MS: 405 (M, 1Cl).

Example 16

16.1

73 mg (0.16 mmol) Methanesulfonic acid4-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl ester in 1 mlDMA were treated with 35 μl (0.5 mmol) azetidine for 48 h. The solutionwas diluted with ether and aqueous Na₂CO₃, the phases were separated andthe inorganic layer was extracted with ether. The combined organicphases were washed with brine, dried over Na₂SO₄. Column chromatographyon silica gel with a gradient CH₂Cl₂ to CH₂Cl₂:MeOH 8:1 gave 22.2 mg(33%)6-(4-Azetidin-1-yl-but-1-ynyl)-3-(4-bromo-phenyl)-benzo[d]isothiazole asbrown oil, MS: 397(MH⁺, 1Br).

16.2

In analogy to example 16.1, Methanesulfonic acid4-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl ester and2-(Methylamino)ethanol were converted to yield2-({4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-methyl-amino)-ethanolas brown oil, MS: 415(MH⁺, 1Br).

16.3

In analogy to example 16.1, Methanesulfonic acid5-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester andAllylmethylamine were converted to yieldAllyl-{5-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-methyl-amineas light yellow solid, MS: 425 (MH⁺, 1Br).

16.4

In analogy to example 16.1, Methanesulfonic acid5-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and2-Methylaminoethanol were converted to yield2-({5-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-methyl-amino)-ethanolas off-white semisolid, MS: 429(MH⁺, 1Br).

16.5

In analogy to example 16.1, Methanesulfonic acid5-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and2-Ethylaminoethanol were converted to yield2-({5-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-ethyl-amino)-ethanolas off-white semisolid, MS: 443 (MH⁺, 1Br).

16.6

In analogy to example 16.1, Methanesulfonic acid5-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester andN-(2-Methoxyethyl)methylamine were converted to yield{5-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-(2-methoxy-ethyl)-methyl-amineas off-white semisolid, MS: 443 (MH⁺, 1Br).

16.7

In analogy to example 16.1, Methanesulfonic acid5-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester andDimethylamine were converted to yield{5-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-dimethyl-amineas off-white semisolid, MS: 399 (MH⁺, 1Br).

16.8

In analogy to example 16.1, Methanesulfonic acid5-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester andazetidine were converted to yield6-(5-Azetidin-1-yl-pent-1-ynyl)-3-(4-bromo-phenyl)-benzo[d]isothiazoleas orange semisolid, MS: 411 (MH⁺, 1Br).

16.9

In analogy to example 16.1, Methanesulfonic acid3-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester andAllylmethylamine (2×2 equivalents) were converted to yieldAllyl-{3-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-methyl-amineas brown oil, MS: 353 (MH⁺, 1Cl).

16.10

In analogy to example 16.1, Methanesulfonic acid3-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester and2-Ethylaminoethanol (2×2 equivalents) were converted to yield2-({3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-ethyl-amino)-ethanol,MS: 371 (MH⁺, 1Cl).

16.11

In analogy to example 16.1, Methanesulfonic acid3-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester andDiethanolamine (2×2 equivalents) were converted to yield2-[{3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-(2-hydroxy-ethyl)-amino]-ethanolas white solid, MS: 387 (MH⁺, 1Cl).

16.12

In analogy to example 16.1, Methanesulfonic acid3-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester andDimethylamine (10 equivalents of a 5.6 M EtOH solution) were convertedto yield{3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-dimethyl-amineas light brown solid, MS: 327 (MH⁺, 1Cl).

Example 17

17.1

150 mg (0.34 mmol) Methanesulfonic acid5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynylester in 1.5 ml DMF were treated with 140 μl (1.7 mmol)N-allylmethylamine at 50° C. for 4 h. The solution was diluted withether and water, the organic phase was washed with 0.5 M NaOH, and driedover Na₂SO₄. Column chromatography on silica gel gave 80 mg (56%)2-(Methyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amino)-ethanolas light yellow, MS: 419(MH⁺).

17.2

In analogy to example 17.1, Methanesulfonic acid3-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester and2-methylaminoethanol were converted to yield2-({3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-methyl-amino)-ethanolas light brown semisolid, MS: 401(MH⁺, 1Br).

17.3

In analogy to example 17.1, Methanesulfonic acid3-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester and2-ethylaminoethanol were converted to yield2-({3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-ethyl-amino)-ethanolas light brown semisolid, MS: 415(MH⁺, 1Br).

17.4

In analogy to example 17.1, Methanesulfonic acid5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynylester and N-allylmethylamine were converted to yieldAllyl-methyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amineas light yellow oil, MS: 415(MH⁺).

17.5

In analogy to example 17.1, Methanesulfonic acid5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynylester and 2-Methoxyethylmethylamine were converted to yield(2-Methoxy-ethyl)-methyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amineas orange oil, MS: 433 (MH⁺).

17.6

In analogy to example 17.1, Methanesulfonic acid5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynylester and dimethylamine were converted to yieldDimethyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amineas off-white solid, MS: 389 (MH⁺).

17.7

In analogy to example 17.1, Methanesulfonic acid5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynylester and 2-Ethylaminoethanol were converted to yield2-(Ethyl-[5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amino)-ethanolas light yellow oil, MS: 433 (MH⁺).

17.8

In analogy to example 17.1, Methanesulfonic acid5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynylester and azetidine were converted to yield6-(5-Azetidin-1-yl-pent-1-ynyl)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazoleas orange oil, MS: 401 (MH⁺).

17.9

In analogy to example 17.1, Methanesulfonic acid3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynylester and 2-Methylaminoethanol were converted to yield2-(Methyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amino)-ethanolas light brown oil, MS: 391 (MH⁺).

17.10

In analogy to example 17.1, Methanesulfonic acid3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynylester and 2-ethylaminoethanol were converted to yield2-(Ethyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amino)-ethanolas light brown oil, MS: 405 (MH⁺).

17.11

In analogy to example 17.1, Methanesulfonic acid3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynylester and N-allylmethylamine were converted to yieldAllyl-methyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amineas orange oil, MS: 387 (MH⁺).

17.12

In analogy to example 17.1, Methanesulfonic acid3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynylester and azetidine were converted to yield6-(3-Azetidin-1-yl-prop-1-ynyl)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazoleas light brown oil, MS: 373 (MH⁺).

17.13

In analogy to example 17.1, Methanesulfonic acid3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynylester and 2-Methoxyethylmethylamine were converted to yield(2-Methoxy-ethyl)-methyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amineas light brown oil, MS: 405 (MH⁺).

17.14

In analogy to example 17.1, Methanesulfonic acid3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynylester and Dimethylamine were converted to yieldDimethyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amineas light brown oil, MS: 361 (MH⁺).

Example 18

A solution of 0.25 mmol (1 equivalent) of the correspondingmethanesulfonic acid in 0.7 ml dry DMA was treated with a solution of0.5 mmol (2 equivalents) of the corresponding secondary amine in 0.15 mldry DMA at room temperature. After 16 h, 2 equivalents of secondaryamine were added again to the solution. The reaction mixture was allowedto stand over night at room temperature, treated with 0.2 ml formic acidand purified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH)/water(0.1% HCOOH), 10% to 95% acetonitrile]. After evaporation, the productwas obtained as a mixture of amino formate and methanesulfonate.

18.1

According to the method in example 18, Methanesulfonic acid5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester andN-Dimethylamine were converted to yield{5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-dimethyl-amine,MS: 355 (MH⁺).

18.2

According to the method in example 18, Methanesulfonic acid5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester andPiperidine were converted to yield3-(4-Chloro-phenyl)-6-(5-piperidin-1-yl-pent-1-ynyl)-benzo[d]isothiazole,MS: 395 (MH⁺).

18.3

According to the method in example 18, Methanesulfonic acid5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester andAzetidine were converted to yield6-(5-Azetidin-1-yl-pent-1-ynyl)-3-(4-chloro-phenyl)-benzo[d]isothiazole,MS: 367 (MH⁺).

18.4

According to the method in example 18, Methanesulfonic acid5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester andN-Methylallylamine were converted to yieldAllyl-{5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-methyl-amine,MS: 381 (MH⁺).

18.5

According to the method in example 18, Methanesulfonic acid5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester andDiethylamine were converted to yield{5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-diethyl-amine,MS: 383 (MH⁺).

18.6

According to the method in example 18, Methanesulfonic acid5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester andDiethanolamine were converted to yield2-[{5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-(2-hydroxy-ethyl)-amino]-ethanol,MS: 415 (MH⁺).

18.7

According to the method in example 18, Methanesulfonic acid5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and2-(Ethylamino)ethanol were converted to yield2-({5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-ethyl-amino)-ethanol,MS: 399 (MH⁺).

Example 19

19.1

100 mg (0.28 mmol))4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol in 2 mlCH₂Cl₂ were treated with 53 μl (0.31 mmol) Huenig's base at 51 μl (0.31mmol) trifluoromethane sulfonic acid anhydride at −15° C. The solutionwas stirred at that temperature for 1 h, additional 10 μLtrifluoromethane sulfonic acid anhydride were added and stirringcontinued for 1 h. 48 μl (0.28 mmol) Huenig's base and 75 μl (0.84 mmol)N-(2-Methoxyethyl)methylamine were added at −15° C. The solution waswarmed to RT and stirred for 1.5 h. The solution was diluted with CH₂Cl₂and washed with Na₂CO₃ solution, brine and dried with Na₂SO₄. Columnchromatography gave 66.1 mg (56%){4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-(2-methoxy-ethyl)-methyl-amineas brown oil, MS: 429 (MH⁺, 1Br).

19.2

In analogy to example 19.1,4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol andDimethylamine were converted to yield{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-dimethyl-amineas light brown semisolid, MS: 385 (MH⁺, 1Br).

19.3

In analogy to example 19.1,4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol andN-Allylmethylamine were converted to yieldAllyl-{4-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-methyl-amineas brown oil, MS: 411 (MH⁺, 1Br).

19.4

In analogy to example 19.1,4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol and2-(Ethylamino)ethanol were converted to yield2-({4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-ethyl-amino)-ethanolas brown oil, MS: 429 (MH⁺, 1Br).

19.5

In analogy to example 19.1,4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-oland Dimethylamine were converted to yieldDimethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-amineas brown oil, MS: 375 (MH⁺).

19.6

In analogy to example 19.1,4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-oland N-allylmethylamine were converted to yieldAllyl-methyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-amineas yellow oil, MS: 401 (MH⁺).

19.7

In analogy to example 19.1,4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-oland 2-Ethylaminoethanol were converted to yield2-(Ethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-amino)-ethanolas light yellow oil, MS: 419 (MH⁺).

19.8

In analogy to example 19.1,4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-oland 2-Methylaminoethanol were converted to yield2-(Methyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-amino)-ethanolas yellow oil, MS: 405 (MH⁺).

19.9

In analogy to example 19.1,4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-oland 2-Methoxyethylmethylamine were converted to yield(2-Methoxy-ethyl)-methyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-amineas light brown oil, MS: 419 (MH⁺).

19.10

In analogy to example 19.1,4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol and2-Ethylaminoethanol were converted to yield2-({4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-ethyl-amino)-ethanolas light yellow oil, MS: 358 (MH⁺, 1Cl).

Example 20

20.1

500 mg (1.5 mmol)3-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-olin 25 ml MeOH were hydrogenated in the presence of 120 mg PtO₂. H₂O,filtration over silica gel and evaporation yielded 360 mg (71%)3-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propan-1-ol,which was directly subjected to the following reaction.

20.2

In analogy to example 20.1,4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-olwas converted to yield4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butan-1-ol, MS:351 (M).

20.3

In analogy to example 20.1, Methanesulfonic acid4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl ester inEtOH/dioxane was converted to yield Methanesulfonic acid4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester as a darkbrown oil, MS: 396 (MH⁺, 1Cl).

20.4

In analogy to example 20.1,3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-yn-1-ol inEtOH/dioxane was converted to yield3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-propan-1-ol as a brownoil, MS: 303 (M, 1Cl).

20.5

In analogy to example 20.1,4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol wasconverted to yield4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butan-1-ol as yellow oil,MS: 361 (M, 1Br).

Example 21

21.1

360 mg (1.07 mmol)3-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propan-1-ol in3 ml CH₂Cl₂ were treated with 100 μl (1.29 mmol) methanesulfonic acidchloride and 450 μl (3.23 mmol) triethylamine at 0° C. The solution wasstirred at RT for 2 h, diluted with CH₂Cl₂ and washed with 1N HCl anddried over Na₂SO₄. Evaporation gave 350 mg (79%) crude Methanesulfonicacid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propylester, which was directly subjected to the following reaction.

21.2

In analogy to example 21.1,4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butan-1-ol andmethanesulfonic acid chloride were converted to yield Methanesulfonicacid 4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butylester, MS: 430 (MH⁺).

21.3

In analogy to example 21.1,3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-propan-1-ol andmethanesulfonic acid chloride were converted to Methanesulfonic acid3-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-propyl ester as anorange oil, MS: 381 (M, 1Cl).

Example 22

22.1

In analogy to example 17.1; Methanesulfonic acid3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl esterand 2-ethylaminoethanol were converted to yield2-(Ethyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl}-amino)-ethanolas light brown oil, MS: 409 (MH⁺).

22.2

In analogy to example 17.1; Methanesulfonic acid3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl esterand Dimethylamine were converted to yieldDimethyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl}-amineas light brown oil, MS: 365 (MH⁺).

22.3

In analogy to example 17.1; Methanesulfonic acid3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl esterand 2-Methylaminoethanol were converted to yield2-(Methyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl}-amino)-ethanolas light brown oil, MS: 395 (MH⁺).

22.4

In analogy to example 17.1; Methanesulfonic acid4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and2-Ethylaminoethanol were converted to yield2-(Ethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-amino)-ethanolas light yellow oil, MS: 423 (MH⁺).

22.5

In analogy to example 17.1; Methanesulfonic acid4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester andDimethylamine were converted to yieldDimethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-amineas yellow oil, MS: 379 (MH⁺).

22.6

In analogy to example 17.1; Methanesulfonic acid4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and2-Methylaminoethanol were converted to yield2-(Methyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-amino)-ethanolas light yellow oil, MS: 409 (MH⁺).

22.7

In analogy to example 17.1; Methanesulfonic acid3-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-propyl ester and2-Ethylaminoethanol were converted to yield2-({3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-propyl}-ethyl-amino)-ethanolas yellow oil, MS: 375 (MH⁺, 1Cl).

Example 23

A solution of 0.25 mmol (1 equivalent) of the correspondingmethanesulfonic acid in 0.7 ml dry DMA was treated with a solution of0.5 mmol (2 equivalents) of the corresponding secondary amine in 0.15 mldry DMA at room temperature. After 16 h, 2 equivalents of secondaryamine were added again to the solution. The reaction mixture was allowedto stand over night at room temperature, treated with 0.2 ml formic acidand purified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH)/water(0.1% HCOOH), 10% to 95% acetonitrile]. After evaporation, the productwas obtained as a mixture of amino formate and methanesulfonate.

23.1

According to the method in example 23, Methanesulfonic acid4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester andN-Methylallylamine were converted to yieldAllyl-{4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-methyl-amine,MS: 371 (MH⁺, 1Cl).

23.2

According to the method in example 23, Methanesulfonic acid4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester andDiethylamine were converted to yield{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-diethyl-amine,MS: 373 (MH⁺, 1Cl).

23.3

According to the method in example 23, Methanesulfonic acid4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester andN-Methylpropylamine were converted to yield{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-methyl-propyl-amine,MS: 373 (MH⁺, 1Cl).

23.4

According to the method in example 23, Methanesulfonic acid4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester andDiethanolamin were converted to yield2-[{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol,MS: 405 (MH⁺, 1Cl).

23.5

According to the method in example 23, Methanesulfonic acid4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and2-Ethylaminoethanol were converted to yield2-({4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-ethyl-amino)-ethanol,MS: 389 (MH⁺, 1Cl).

23.6

According to the method in example 23, Methanesulfonic acid4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester andN-(2-Methoxyethyl)ethylamine were converted to yield{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-ethyl-(2-methoxy-ethyl)-amine,MS: 403 (MH⁺, 1Cl).

23.7

According to the method in example 23, Methanesulfonic acid4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester andTrimethyleneamine were converted to yield6-(4-Azetidin-1-yl-butyl)-3-(4-chloro-phenyl)-benzo[d]isothiazole, MS:357 (MH⁺, 1Cl).

Example 24

24.1

Method A: 75 mg (0.2 mmol)2-({3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-ethyl-amino)-ethanolin 2 ml MeOH with 0.012 ml (0.2 mmol) AcOH were hydrogenated in thepresence of 7 mg Pd/C 10% (16 h), filtration over decalite andevaporation yielded 58 mg (66%)Z-2-({3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-allyl}-ethyl-amino)-ethanolacetate as light brown oil, MS: 373 (MH⁺, 1Cl).

24.2

Method B: 80 mg (0.25 mmol){3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-dimethyl-aminein 2 ml EtOH were hydrogenated in the presence of 20 mg PtO₂. H₂O,purification by flash silica gel column (CH₂Cl₂/MeOH 9:1) yielded 43 mg(53%){3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-propyl}-dimethyl-amineas a colorless oil, MS: 331 (MH⁺, 1Cl).

Example 25

25.1

10.09 g (70.5 mmol) 3-mercaptoanisole were added to a freshly preparedsolution of 4.6 g (70.5 mmol) KOH in 75 ml ethanol and 30 ml water. Overa period of 30 min, 20.0 g (70.5 mmol) 2,4-dibromoacetophenone in 150EtOAc were added at 0° C. and the solution was stirred at RT over night.The suspension was concentrated and dissolved in EtOAc and water. Theinorganic phase was extracted with EtOAC, the combined organic phaseswere washed with water and brine and dried over Na₂SO₄. Evaporationyielded 25.1 g (quant)1-(4-Bromo-phenyl)-2-(3-methoxy-phenylsulfanyl)-ethanone as whitecrystalline, MS: 336(M, 1Br). (In analogy to Jones, Charles D.;Jevnikar, Mary G.; Pike, Andrew J.; Peters, Mary K.; Black, Larry J.;Thompson, Allen R.; Falcone, Julie F.; Clemens, James A. Antiestrogens.2. Structure-activity studies in a series of3-aroyl-2-arylbenzo[b]thiophene derivatives leading to[6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanonehydrochloride (LY 156758), a remarkably effective estrogen antagonistwith only minimal intrinsic estrogenicity. J. Med. Chem. (1984), 27(8),1057-66.)

25.2

60 g polyphosphoric acid were heated to 80° C. 11.85 g (35.14 mmol)1-(4-Bromo-phenyl)-2-(3-methoxy-phenylsulfanyl)-ethanone were added insmall portions, keeping the temperature below 100° C. The reactionmixture was stirred at 85° C. for 2 h, cooled to 70° C. and added to icewater. The aqueous phase was extracted with EtOAc three times, theorganic phase was washed with brine and dried over Na₂SO₄. The solid wascrystallized from EtOAc:MeOH to give 6.3 g (56%)3-(4-Bromo-phenyl)-6-methoxy-benzo[b]thiophene as light yellow solid.MS: 318 (M, 1Br).

25.3

7.4 g (23.17 mmol) 3-(4-Bromo-phenyl)-6-methoxy-benzo[b]thiophene in 47ml acetic acid were treated with 27 ml (62% aq) HBr at 125° C. for 4 h.The solution was concentrated in vacuo and the residue was dissolved inNaHCO₃ and EtOAc. Prior to extraction with EtOAc the pH was adjustedwith 2M NaOH (pH 8). The combined organic phases were washed with brineand dried with Na₂SO₄. Trituration with hexane gave 6.96 g (98%)3-(4-Bromo-phenyl)-benzo[b]thiophen-6-ol as light green solid, MS: 304(M, 1Br).

Example 26

26.1

14.27 ml (115.0 mmol) 3-mercaptoanisole were added to a solution of 7.3g (115.0 mmol) KOH in 120 ml ethanol and 50 ml water. 25.0 g (115.2mmol) 4-fluorophenacyl bromide in 120 ml EtOAc were added slowly at 0°C. and the solution was stirred at RT over night. The suspension wasconcentrated and dissolved in EtOAc and water. The inorganic phase wasextracted with EtOAc, the combined organic phases were washed with waterand brine and dried over Na₂SO₄. Evaporation yielded 33.2 g crude1-(4-Fluoro-phenyl)-2-(3-methoxy-phenylsulfanyl)-ethanone as lightyellow liquid.

26.2

The crude product of experiment 26.1 was dissolved in toluene andevaporated three times prior to the reaction. To the resulting solid 305ml (1.2 mol) BF₃.Et₂O were added slowly and the solution was stirred atRT over night. This solution was added slowly to NaOH, and the pH wasadjusted to pH 7. The solution was extracted with CH₂Cl₂, the organicphase was washed with brine and dried over Na₂SO₄, yielding 29.96 gcrude 3-(4-Fluoro-phenyl)-6-methoxy-benzo[b]thiophene.

26.3

29.96 g 3-(4-Fluoro-phenyl)-6-methoxy-benzo[b]thiophene in 230 ml aceticacid were treated with 130 ml (62% aq) HBr at 125° C. for 4 h. Thesolution was added slowly to a cooled solution of 210 g NaOH in 600 mlwater, the pH was adjusted to 8-9, and the inorganic phase was extractedwith EtOAc. The combined organic phases were washed with brine and driedwith Na₂SO₄. Column chromatography on silica gel with hexane:EtOAc 4.1yielded 20.0 g (73%) 3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-ol as lightbrown solid, MS: 244(M).

26.4

In analogy to examples 26.1-26.3, 3-mercaptoanisole and2,4′-dibromopropiophenone were converted to yield3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophen-6-ol as colorless amorphoussolid, MS: 318 (M, 1Br).

26.5

In analogy to examples 26.1-26.3, 3-Mercaptoanisole and2-Bromo-1-(4-trifluoromethyl-phenyl)-propan-1-one were converted toyield 2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-ol ascolorless amorphous solid, MS: 308 (M).

Example 27

27.1

2.0 g (6.55 mmol) 3-(4-Bromo-phenyl)-benzo[b]thiophen-6-ol in 25 mlacetone were treated with 5.89 g (42.6 mmol, 6.5 eq) K₂CO₃ and 2.0 ml(16.38 mmol, 2.5 eq) 1,4-dibromobutane. The reaction mixture was stirredat 45° C. for 10 h, filtered and evaporated. The excess of dibromide wasremoved in vacuo to yield 2.7 g crude6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene, MS: 439 (M).

27.2

In analogy to example 27.1, 3-(4-Bromo-phenyl)-benzo[b]thiophen-6-ol and1,3-dibromopropane were converted to yield3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[b]thiophene, MS: 424 (M,2Br).

27.3

In analogy to example 27.1, 3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-oland 1,3-dibromopropane were converted to yield6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene, MS: 364 (M,1Br).

27.4

In analogy to example 27.1, 3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-oland 1,4-dibromobutane were converted to yield6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene, MS: 378 (M,1Br).

27.5

In analogy to example 27.1,3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophen-6-ol and 1,4-dibromobutanewere converted to yield6-(4-bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene ascolorless oil, MS: 452 (M, 2Br).

27.6

In analogy to example 27.1,2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-ol and1,4-dibromobutane were converted to yield6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiopheneas colorless oil, MS: 443 (MH⁺, 1Br).

Example 28

28.1

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene andN,N-dimethylamine in ethanol were converted to yield[4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl]-dimethyl-amineas light yellow semisolid, MS: 404 (MH⁺, 1Br).

28.2

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene andN-Allylmethylamine were converted to yieldAllyl-[4-[3-(4-bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl]-methyl-amineas light yellow oil, MS: 430(MH⁺, 1Br).

28.3

In analogy to example 3.1,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[b]thiophene anddiethanolamine were converted to yield2-[{3-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-(2-hydroxy-ethyl)-amino]-ethanolas light yellow oil, MS: 450 (MH⁺, 1Br).

28.4

In analogy to example 3.1,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[b]thiophene andbis(2-methoxyethyl)amine were converted to yield{3-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-bis-(2-methoxy-ethyl)-amineas light brown oil, MS: 478 (MH⁺, 1Br).

Example 29

1 eq of the corresponding bromide was treated with 3 eq of thecorresponding amine in DMA (4-10 ml/mmol bromide) at RT until nostarting material could be detected with TLC. The solution wasconcentrated and the residue was redissolved in CH₂Cl₂/5% aqueousNaHCO₃. The phases were separated, and the inorganic phase was extractedwith CH₂Cl₂, the combined organic phases were washed with brine, andwere dried over Na₂SO₄. The crude material was purified by flashchromatography. To yield the corresponding hydrochlorides, the freeamines were treated with HCl in MeOH.

29.1

According to the method in example 29,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene and2-(methylamino)ethanol were converted to yield2-({4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amino)-ethanol.hydrochlorideas light brown oil, MS: 434 (MH⁺, 1Br).

29.2

According to the method in example 29,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene andN-(2-methoxyethyl)methylamine were converted to yield{4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine.hydrochlorideas light brown semisolid, MS: 448 (MH⁺, 1Br).

29.3

According to the method in example 29,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene and morpholinewere converted to yield4-{4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-morpholine.hydrochlorideas light brown semisolid, MS: 446 (MH⁺, 1Br).

29.4

According to the method in example 29,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene and2-(ethylamino)ethanol were converted to yield2-({4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-amino)-ethanol.hydrochlorideas orange oil, MS: 448 (MH⁺, 1Br).

29.5

According to the method in example 29,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene and pyrrolidinewere converted to yield1-{4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-pyrrolidine.hydrochlorideas grey semisolid, MS: 430 (MH⁺, 1Br).

29.6

According to the method in example 29,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene and azetidinewere converted to yield1-{4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-azetidine.hydrochlorideas light yellow oil, MS: 416 (MH⁺, 1Br).

29.7

According to the method in example 29,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene andmethylisopropylamine were converted to yield{4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-isopropyl-methyl-amine-hydrochlorideas white foam, MS: 432 (MH⁺, 1Br).

29.8

According to the method in example 29,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene and diethylaminewere converted to yield{4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-diethyl-amine.hydrochlorideas orange oil, MS: 432 (MH⁺, 1Br).

29.9

According to the method in example 29,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene anddiethanolamine were converted to yield2-[{4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanolas light yellow oil, MS: 464 (MH⁺, 1Br).

29.10

According to the method in example 29,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene andbis(2-methoxyethyl)amine were converted to yield{4-[3-(4-Bromo-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-bis-(2-methoxy-ethyl)-amineas light brown oil, MS: 492 (MH⁺, 1Br).

Example 30

30.1

In analogy to example 3.1,6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene andN-allylmethylamine were converted to yieldAllyl-{3-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl]-methyl-amineas colorless oil, MS: 356 (MH⁺).

30.2

In analogy to example 3.1,6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene anddimethylamine were converted to yield{3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-dimethyl-amineas colorless oil, MS: 330 (MH⁺).

30.3

In analogy to example 3.1,6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and2-(methylamino)ethanol were converted to yield2-({3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-methyl-amino)-ethanolas colorless oil, MS: 360 (MH⁺).

30.4

In analogy to example 3.1,6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene andN-(2-methoxyethyl)methylamine were converted to yield{3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-(2-methoxy-ethyl)-methyl-amineas colorless oil, MS: 374 (MH⁺).

30.5

In analogy to example 3.1,6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and2-(ethylamino)ethanol were converted to yield2-(Ethyl-{3-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-amino)-ethanolas colorless oil, MS: 374 (MH⁺).

30.6

In analogy to example 3.1,6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene andN-(2-methoxyethyl)ethylamine were converted to yieldEthyl-{3-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-(2-methoxy-ethyl)-amineas colorless oil, MS: 388 (MH⁺).

30.7

In analogy to example 3.1,6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene anddiethanolamine were converted to yield2-[{3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-(2-hydroxy-ethyl)-amino]-ethanolas colorless oil, MS: 390 (MH⁺).

30.8

In analogy to example 3.1,6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene andbis(2-methoxyethyl)amine were converted to yield{3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-bis-(2-methoxy-ethyl)-amineas colorless oil, MS: 418 (MH⁺).

30.9

In analogy to example 3.1,6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene andpyrrolidine were converted to yield1-{3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-pyrrolidineas colorless oil, MS: 356 (MH⁺).

30.10

In analogy to example 3.1,6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and azetidinewere converted to yield1-{3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-azetidine ascolorless oil, MS: 342 (MH⁺).

30.11

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene andN-allylmethylamine were converted to yieldAllyl-{4-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amineas colorless oil, MS: 370 (MH⁺).

30.12

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene anddimethylamine were converted to yield{4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-dimethyl-amineas white semisolid, MS: 344 (MH⁺).

30.13

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and2-(methylamino)ethanol were converted to yield2-({4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amino)-ethanolas colorless oil, MS: 374 (MH⁺).

30.14

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene andN-(2-methoxyethyl)methylamine were converted to yield{4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amineas colorless oil, MS: 388 (MH⁺).

30.15

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and2-(ethylamino)ethanol were converted to yield2-(Ethyl-{4-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-amino)-ethanolas colorless oil, MS: 388 (MH⁺).

30.16

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene andN-(2-methoxyethyl)ethylamine were converted to yieldEthyl-{4-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-methoxy-ethyl)-amineas colorless oil, MS: 402 (MH⁺).

30.17

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene anddiethanolamine were converted to yield2-[{4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanolas white semisolid, MS: 404 (MH⁺).

30.18

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene andbis(2-methoxyethyl)amine were converted to yield{4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-bis-(2-methoxy-ethyl)-amineas colorless oil, MS: 432 (MH⁺).

30.19

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and pyrrolidinewere converted to yield1-{4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-pyrrolidineas white semisolid, MS: 370 (MH⁺).

30.20

In analogy to example 3.1,6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and azetidinewere converted to yield1-{4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-azetidine ascolorless oil, MS: 356 (MH⁺).

Example 31

A solution of 0.25 mmol (1 equivalent) of the corresponding bromide in0.7 ml dry DMA was treated with a solution of 0.5 mmol (2 equivalents)of the corresponding secondary amine in 0.15 ml dry DMA at roomtemperature. After 16 h, additional 2 equivalents of secondary aminewere added to the solution. The reaction mixture was allowed to standover night at room temperature, treated with 0.2 ml formic acid andpurified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH)/water(0.1% HCOOH), 10% to 95% acetonitrile]. After evaporation, the productwas obtained as a mixture of amino hydrobromide and formate.

31.1

According to the method in example 31,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene andAllyl-methyl-amine were converted to yieldAllyl-{4-[3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amine,MS: 444 (MH⁺, 1Br).

31.2

According to the method in example 31,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene andDimethylamine were converted to yield{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-dimethyl-amine,MS: 418 (MH⁺, 1Br).

31.3

According to the method in example 31,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene andEthyl-(2-hydroxy-ethyl)-amine were converted to yield2-({4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-amino)-ethanol,MS: 462 (MH⁺, 1Br).

31.4

According to the method in example 31,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene andDiethylamine were converted to yield{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-diethyl-amine,MS: 446 (MH⁺, 1Br).

31.5

According to the method in example 31,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene andpiperidine were converted to yield1-{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-piperidine,MS: 458 (MH⁺, 1Br).

31.6

According to the method in example 31,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene andAzetidine were converted to yield1-{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-azetidine,MS: 430 (MH⁺, 1Br).

31.7

According to the method in example 31,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene and2-(hydroxy-ethyl)-amino-ethanol were converted to yield2-[{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol,MS: 478 (MH⁺, 1Br).

31.8

According to the method in example 31,6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiopheneand 4-hydroxy-piperidine were converted to yield1-{4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-piperidin-4-olas yellowish oil, MS: 464 (MH⁺).

31.9

According to the method in example 31,6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiopheneand N-propyl amine were converted to yield{4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-propyl-amineas yellowish oil, MS: 422 (MH⁺).

31.10

According to the method in example 31,6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiopheneand ethanolamine were converted to yield2-{4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butylamino}-ethanolas colorless amorphous solid, MS: 424 (MH⁺).

31.11

According to the method in example 31,6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiopheneand 2-ethylamino-ethanol were converted to yield2-(Ethyl-{4-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-amino)-ethanolas yellowish oil, MS: 452 (MH⁺).

31.12

According to the method in example 31,6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiopheneand N-allyl-methylamine were converted to yieldAllyl-methyl-{4-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-amineas yellowish oil, MS: 434 (MH⁺).

31.13

According to the method in example 31,6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiopheneand piperidine were converted to yield1-{4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-piperidineas yellowish oil, MS: 448 (MH⁺).

31.14

According to the method in example 31,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene andN-(2-methoxy-ethyl)-ethylamine were converted to yield{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amineas yellowish oil, MS: 476 (MH⁺, 1Br).

31.15

According to the method in example 31,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene anddimethylamine were converted to yield{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-dimethyl-amineas yellowish oil, MS: 418 (MH⁺, 1Br).

Example 32

32.1

1.3 g (2.95 mmol)6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene in 140 ml aceticacid were warmed to 50° C. and 1.36 g (8.9 mmol) sodium perborate wereadded in portions. The reaction mixture was stirred at that temperaturefor 18 h, concentrated and dissolved in water, and extracted with EtOAcand CH₂Cl₂. The combined organic phases were washed with brine and driedover Na₂SO₄. Column chromatography on silica gel with EtOAc:hexane 1:4yielded 802 mg (67%)6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene 1,1-dioxide aslight yellow solid, MS: 472 (MH⁺, 1Br).

32.2

In analogy to example 32.1,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[b]thiophene was convertedto yield 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[b]thiophene1,1-dioxide as light yellow solid, MS: 458 (MH⁺, 1Br).

32.3

In analogy to example 32.1,6-(4-bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene wasconverted to yield6-(4-bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene1,1-dioxide as colorless solid, MS: 484 (M, 2Br).

32.4

In analogy to example 32.1,6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophenewas converted to yield6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene1,1-dioxide as colorless solid, MS: 475 (MH⁺, 1Br).

Example 33

1 eq of the corresponding bromide was treated with 3 eq of thecorresponding amine in DMA (4-10 ml/mmol bromide) at RT until nostarting material could be detected with TLC. The solution wasconcentrated and the residue was redissolved in CH₂Cl₂/5% aqueousNaHCO₃. The phases were separated, and the inorganic phase was extractedwith CH₂Cl₂, the combined organic phases were washed with brine, andwere dried over Na₂SO₄. The crude material was purified by flashchromatography. To yield the corresponding hydrochlorides, the freeamines were treated with HCl in MeOH.

33.1

According to the method in example 33,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[b]thiophene 1,1-dioxide andN-Allylmethylamine were converted to yieldAllyl-{3-[3-(4-bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-propyl}-methyl-amine as light yellow solid,MS: 448(MH⁺, 1Br).

33.2

According to the method in example 33,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[b]thiophene 1,1-dioxide andDimethylamine were converted to yield{3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-propyl}-dimethyl-amine as off-white solid,MS: 422 (MH⁺, 1Br).

33.3

According to the method in example 33,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[b]thiophene 1,1-dioxide andN-Methylaminoethanol were converted to yield2-({3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-propyl}-methyl-amino)-ethanol as off-whitesemisolid, MS: 452 (MH⁺, 1Br).

33.4

According to the method in example 33,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[b]thiophene 1,1-dioxide andN-Ethylaminoethanol were converted to yield2-({3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-propyl}-ethyl-amino)-ethanol as light yellowsemisolid, MS: 466(MH⁺, 1Br).

33.5

According to the method in example 33,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[b]thiophene 1,1-dioxide andN-(2-Methoxyethyl)methylamine were converted to yield{3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-propyl}-(2-methoxy-ethyl)-methyl-amine asoff-white solid, MS: 466 (MH⁺, 1Br).

33.6

According to the method in example 33,3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[b]thiophene 1,1-dioxide andazetidine were converted to yield1-{3-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-propyl}-azetidine as off-white solid, MS:434 (MH⁺, 1Br).

33.7

According to the method in example 33,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene 1,1-dioxide andN-Allylmethylamine were converted to yieldAllyl-{4-[3-(4-bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amine as off-white semisolid,MS: 462 (MH⁺, 1Br).

33.8

According to the method in example 33,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene 1,1-dioxide andDimethylamine were converted to yield{4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-dimethyl-amine as light yellowsemisolid, MS: 436 (MH⁺, 1Br).

33.9

According to the method in example 33,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene 1,1-dioxide andN-Methylaminoethanol were converted to yield2-({4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amino)-ethanol as off-whitesolid, MS: 466 (MH⁺, 1Br).

33.10

According to the method in example 33,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene 1,1-dioxide andN-Ethylaminoethanol were converted to yield2-({4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-amino)-ethanol as off-whitesolid, MS: 480 (MH⁺, 1Br).

33.11

According to the method in example 33,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene 1,1-dioxide andN-(2-Methoxyethyl)methylamine were converted to yield{4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-(2-methoxy-ethyl)-methyl-amine aslight yellow semisolid, MS: 480 (MH⁺, 1Br).

33.12

According to the method in example 33,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene 1,1-dioxide andazetidine were converted to yield1-{4-[3-(4-Bromo-phenyl)-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-azetidine as off-white solid, MS: 434(MH⁺, 1Br).

Example 34

A solution of 0.25 mmol (1 equivalent) of the corresponding bromide in0.7 ml dry DMA was treated with a solution of 0.5 mmol (2 equivalents)of the corresponding secondary amine in 0.15 ml dry DMA at roomtemperature. After 16 h, additional 2 equivalents of secondary aminewere added to the solution. The reaction mixture was allowed to standover night at room temperature, treated with 0.2 ml formic acid andpurified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH)/water(0.1% HCOOH), 10% to 95% acetonitrile]. After evaporation, the productwas obtained as a mixture of amino hydrobromide and formate.

34.1

According to the method in example 34,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene1,1-dioxide and N-Methylallylamine were converted to yieldAllyl-{4-[3-(4-bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amine, MS: 476 (MH⁺, 1Br).

34.2

According to the method in example 34,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene1,1-dioxide and Diethylamine were converted to yield{4-[3-(4-Bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-diethyl-amine, MS: 478 (MH⁺, 1Br).

34.3

According to the method in example 34,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene1,1-dioxide and N-Methylpropylamine were converted to yield{4-[3-(4-Bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-methyl-propyl-amine, MS: 478 (MH⁺,1Br).

34.4

According to the method in example 34,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene1,1-dioxide and Diethanolamine were converted to yield2-[{4-[3-(4-Bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol, MS:510 (MH⁺, 1Br).

34.5

According to the method in example 34,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene1,1-dioxide and 2-Ethylaminoethanol were converted to yield2-({4-[3-(4-Bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-amino)-ethanol, MS: 494 (MH⁺,1Br).

34.6

According to the method in example 34,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene1,1-dioxide and N-(2-Methoxyethyl)ethylamine were converted to yield{4-[3-(4-Bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine, MS:508 (MH⁺, 1Br).

34.7

According to the method in example 34,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene1,1-dioxide and Trimethyleneamine were converted to yield1-{4-[3-(4-Bromo-phenyl)-2-methyl-1,1-dioxo-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-azetidine, MS: 462 (MH⁺, 1Br).

34.8

According to the method in example 34,6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene1,1-dioxide and 2-ethylamino-ethanol were converted to yield2-(Ethyl-{4-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-amino)-ethanol as colorless oil, MS:484 (MH⁺).

34.9

According to the method in example 34,6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene1,1-dioxide and diethylamine were converted to yieldDiethyl-{4-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-amine as yellowish solid, MS: 468(MH⁺).

34.10

According to the method in example 34,6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene1,1-dioxide and N-methyl propyl-amine were converted to yieldMethyl-{4-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-propyl-amine as yellowish oil, MS:468 (MH⁺).

34.11

According to the method in example 34,6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene1,1-dioxide and N-(2-methoxy-ethyl)ethyl-amine were converted to yieldEthyl-(2-methoxy-ethyl)-{4-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-amine as yellowish oil, MS: 498(MH⁺).

34.12

According to the method in example 34,6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene1,1-dioxide and diethanol-amine were converted to yield2-((2-Hydroxy-ethyl)-{4-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l6-benzo[b]thiophen-6-yloxy]-butyl}-amino)-ethanol as colorless oil, MS:500 (MH⁺).

Example 35

35.1

To 7.0 g (15.6 mmol)2-({4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanolin 20 ml DMF were added 1.9 g (28.0 mmol, 1.8 eq) imidazole, followed by3.3 g (21.8 mmol, 1.4 eq) tert-butyldimethylchlorosilane in 20 ml DMF at0° C. The solution was stirred at 50° C. for 6 h, and at RT for 48 h.Additional 235 mg (1.5 mmol, 0.1 eq) tert-butyldimethylchlorosilane wereadded and the solution was stirred at 50° C. for 2 h. The solution waspoured on an aqueous solution of NaHCO₃. The inorganic layer wasextracted with ether, and the combined organic phases were washed withbrine and dried over Na₂SO₄. Column chromatography on silica gel withCH₂Cl₂:MeOH 95:5 gave 6.5 g (74%){4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amineas brown oil, MS: 563 (MH⁺, 1Br).

35.2

Under argon a flask was charged with 26.0 mg (0.03 mmol, 0.05 eq)tris(Dibenzylideneacetone) dipalladium, 16.9 mg (0.06 mmol, 0.1 eq)2(di-tertbutylphosphino)biphenyl and 92.8 mg (0.97 mmol, 1.7 eq) sodiumtert-butylate, evacuated and backfilled with argon. 320 mg (0.57 mmol)4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-aminein 3 ml toluene were added, followed by a solution of 0.14 ml (1.4 mmol,2.5 eq) piperidine in 3 ml toluene. The solution was heated to 80° C.for 2d. The mixture was diluted with EtOAc and a saturated solution ofNa₂CO₃ was added. The inorganic layer was extracted with EtOAc. Thecombined organic phases were washed with brine and dried over Na₂SO₄.Column chromatography yielded 248 mg (77%)[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-{4-[3-(4-piperidin-1-yl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amineas yellow oil, MS: 568 (MH⁺).

35.3

In analogy to example 35.2,4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amineand Morpholine were converted to yield[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-{4-[3-(4-morpholin-4-yl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amineas yellow oil, MS: 570 (MH⁺).

35.4

In analogy to example 35.2,4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amineand N-Methylaniline were converted to yield{4-[6-(4-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amino}-butoxy)-benzo[d]isothiazol-3-yl]-phenyl}-methyl-phenyl-amineas yellow oil, MS: 590 (MH⁺).

35.5

In analogy to example 35.2,4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amineand piperazine were converted to yield[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-{4-[3-(4-piperazin-1-yl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amineas orange oil, MS: 569 (MH⁺).

35.6

In analogy to example 35.2,4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amineand 1-acetylpiperazine were converted to yield1-(4-{4-[6-(4-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amino}-butoxy)-benzo[d]isothiazol-3-yl]-phenyl}-piperazin-1-yl)-ethanoneas orange oil, MS: 611 (MH⁺).

35.7

In analogy to example 35.2,4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amineand benzylamine were converted to yieldBenzyl-{4-[6-(4-{[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amino}-butoxy)-benzo[d]isothiazol-3-yl]-phenyl}-amineas orange oil, MS: 590 (MH⁺).

35.8

220 mg (0.39 mmol)[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-{4-[3-(4-piperidin-1-yl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-aminein 5 ml THF were treated with 0.6 ml 1M TBAF in THF for 1 h at RT. Thesolution was concentrated and the crude product subjected to columnchromatography on silica gel with CH₂Cl₂:MeOH 9:1 to give 146 mg (83%)2-(Ethyl-{4-[3-(4-piperidin-1-yl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanolas yellow oil, MS: 454 (MH⁺).

35.9

In analogy to example 35.8,[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-{4-[3-(4-morpholin-4-yl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-aminewere converted to yield2-(Ethyl-{4-[3-(4-morpholin-4-yl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanolas yellow oil, MS: 456 (MH⁺).

35.10

In analogy to example 35.8,{4-[6-(4-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amino}-butoxy)-benzo[d]isothiazol-3-yl]-phenyl}-methyl-phenyl-aminewere converted to yield2-[Ethyl-(4-{3-[4-(methyl-phenyl-amino)-phenyl]-benzo[d]isothiazol-6-yloxy}-butyl)-amino]-ethanolas yellow oil, MS: 476 (MH⁺).

35.11

In analogy to example 35.8,[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-{4-[3-(4-piperazin-1-yl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-aminewere converted to yield2-(Ethyl-{4-[3-(4-piperazin-1-yl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanolas colorless oil, MS: 455 (MH⁺).

35.12

In analogy to example 35.8,1-(4-{4-[6-(4-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amino}-butoxy)-benzo[d]isothiazol-3-yl]-phenyl}-piperazin-1-yl)-ethanonewere converted to yield1-{4-[4-(6-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-benzo[d]isothiazol-3-yl)-phenyl]-piperazin-1-yl}-ethanoneas colorless oil, MS: 497 (MH⁺).

35.13

In analogy to example 35.8,Benzyl-{4-[6-(4-{[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amino}-butoxy)-benzo[d]isothiazol-3-yl]-phenyl}-aminewere converted to yield2-({4-[3-(4-Benzylamino-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanolas yellow oil, MS: 476 (MH⁺).

35.14

Under argon a flask was charged with 20.3 mg (0.02 mmol, 0.05 eq)tris(dibenzylideneacetone) dipalladium, 13.2 mg (0.04 mmol, 0.1 eq)2(di-tertbutylphosphino)biphenyl and 38.7 mg (0.89 mmol, 2 eq) sodiumhydride (55% in mineral oil), evacuated and backfilled with argon. 250mg (0.44 mmol)4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-aminein 4 ml toluene were added, followed by a solution of 0.031 ml (0.75mmol, 1.7 eq) methanol in 2 ml toluene. The solution was heated to 80°C. for 2 d. The mixture was diluted with EtOAc and a saturated solutionof Na₂CO₃. The inorganic layer was extracted with EtOAc. The combinedorganic phases were washed with brine and dried over Na₂SO₄. Columnchromatography on silica gel with CH₂Cl₂:MeOH 95:5 yielded 174 mg lightyellow oil which was dissolved in 5 ml THF and was treated with 0.53 ml1M Bu₄NF in THF at RT for 1 h. The solution was concentrated and theresidue purified by column chromatography to yield2-{Ethyl-[4-(3-phenyl-benzo[d]isothiazol-6-yloxy)-butyl]-amino}-ethanolas light yellow oil, MS: 371 (MH⁺).

35.15

Under argon a flask was charged with 10.0 mg (0.01 mmol, 0.03 eq)tris(dibenzylideneacetone) dipalladium, 10 mg (0.02 mmol, 0.05 eq) R(+)2,2′-Bis(diphenylphosphino)-1,1′-Binaphtyl and 47.7 mg (0.5 mmol, 1.4eq) sodium tert-butylate, evacuated and backfilled with argon. 200 mg(0.35 mmol)4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-aminein 4 ml toluene were added, followed by a solution of 0.071 ml (0.4mmol, 1.2 eq) benzophenone imine in 2 ml toluene. The solution washeated to 80° C. over night. The mixture was diluted with EtOAc andwater. The inorganic layer was extracted with EtOAc. The combinedorganic phases were washed with brine and dried over Na₂SO₄.

The residue was dissolved in 2 ml MeOH, 10 mg 10% Pd/C and 336 mg (5.3mmol) ammonium formate were added and the reaction mixture was stirredat 60° C. for 3 h. Additional ammonium formate was added in portionsuntil no starting material could be detected. The solution was filteredover decalite and evaporated.

The crude product was dissolved in 1.5 ml THF and was treated with 0.24ml 1M Bu₄NF in THF at RT for 1 h. The solution was concentrated and theresidue purified by ion exchange chromatography to yield 40 mg (29%, 3steps)2-({4-[3-(4-Amino-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanolas orange oil, MS: 386(MH⁺).

Examples 36

36.1

A flask was charged with 31.1 mg (0.04 mmol, 0.05 eq)bis(triphenylphosphine) palladium(II) chloride, evacuated and backfilledwith argon. 500 mg (0.89 mmol)4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amineand 7.0 mg (0.03 mmol, 0.03 eq) triphenylphosphine in 5 ml piperidinewere added, and the solution stirred for 20 min. 1.7 mg (0.01 mmol, 0.01eq) CuI were added, followed by 113 μl (1.06 mmol, 1.2 eq)1-Dimethylamino-2-propyne. The solution was stirred at 50° C. over nightand at 70° C. for 1 h. The mixture was poured on water and EtOAc, thelayers were separated and the inorganic layer was extracted with EtOAc.The combined organic phases were washed with brine and dried overNa₂SO₄. Column chromatography on silica gel with CH₂Cl₂:MeOH 95:5yielded 350 mg (70%)(3-{4-[6-(4-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amino}-butoxy)-benzo[d]isothiazol-3-yl]-phenyl}-prop-2-ynyl)-dimethyl-amineas brown oil.

350 mg (0.62 mmol)(3-{4-[6-(4-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amino}-butoxy)-benzo[d]isothiazol-3-yl]-phenyl}-prop-2-ynyl)-dimethyl-aminein 5 ml THF were treated with 0.92 ml 1M Bu₄NF in THF at RT for 1 h. Thesolution was concentrated and the residue was purified by columnchromatography on silica gel to give 185 mg (66%)2-[(4-{3-[4-(3-Dimethylamino-prop-1-ynyl)-phenyl]-benzo[d]isothiazol-6-yloxy}-butyl)-ethyl-amino]-ethanolas light brown oil, MS: 452 (MH⁺).

36.2

In analogy to example 36.1,{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amineand 2-Propyn-1-ol were converted to yield3-[4-(6-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-benzo[d]isothiazol-3-yl)-phenyl]-prop-2-yn-1-olas yellow oil, MS: 425 (MH⁺).

36.3

In analogy to example 36.1,{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amineand N-Methylpropargylamine were converted to yield2-[Ethyl-(4-{3-[4-(3-methylamino-prop-1-ynyl)-phenyl]-benzo[d]isothiazol-6-yloxy}-butyl)-amino]-ethanolas brown oil, MS: 438 (MH⁺).

Example 37

37.1

To 14.3 ml (146.3 mmol) 2-Ethylaminoethanol in 60 ml THF were added 362mg (3.7 mmol) CuCl, followed by 7.5 g (73.1 mmol)3-Chloro-3-methyl-1-butyne. The solution was stirred at RT for 2 h, thesolvent was removed and the residue dissolved in ether/2M HCl. Thephases were separated and after addition of Na₂CO₃ to the aqueous phase(pH9), it was extracted with ether. The ether phase was dried overNa₂SO₄ and concentrated. Distillation by Kugelrohr yielded2-[(1,1-Dimethyl-prop-2-ynyl)-ethyl-amino]-ethanol as colorless oil, MS:155 (M).

37.2

In analogy to example 37.1, 3-Chloro-3-methyl-1-butyne andAllylmethylamine were converted to yieldAllyl-(1,1-dimethyl-prop-2-ynyl)-methyl-amine as white solid, MS:137(M).

37.3

In analogy to example 37.1, 3-Chloro-3-methyl-1-butyne andN-(2-Methoxyethyl)methylamine were converted to yield(1,1-Dimethyl-prop-2-ynyl)-(2-methoxy-ethyl)-methyl-amine as colorlessoil, MS: 155 (M).

37.4

In analogy to example 37.1, 3-Chloro-3-methyl-1-butyne andN-(2-Methoxyethyl)ethylamine were converted to yield(1,1-Dimethyl-prop-2-ynyl)-ethyl-(2-methoxy-ethyl)-amine as colorlessoil, MS: 170 (MH⁺).

37.5

According to Ishihara, Kazuaki; Kubota, Manabu; Kurihara, Hideki;Yamamoto, Hisashi. Scandium Trifluoromethanesulfonate as an ExtremelyActive Lewis Acid Catalyst in Acylation of Alcohols with Acid Anhydridesand Mixed Anhydrides. J. Org. Chem. (1996), 61(14), 4560-4567.

To 3.1 g (25 mmol) 1-ethynyl-1-cyclohexanol in 25 ml acetonitrile wereadded 7.1 ml (75 mmol, 3 eq) acetic anhydride at −20° C. 12.3 mg (0.03mmol) scandiumtriflate in 300 μl THF were added and the solution wasstirred for 2 h. Additional 12.3 mg (0.03 mmol) scandiumtriflate in 300μl THF were added and stirring was continued for 30 min. A saturatedaqueous solution of NaHCO₃ and ether were added. The layers wereseparated and the inorganic one was extracted with ether. The combinedorganic phases were washed with brine and dried over Na₂SO₄. Evaporationyielded 4.6 g crude 1-ethynylcyclohexyl acetate as colorless oil, MS:166 (M).

37.6

Analogously to Imada, Yasushi; Yuasa, Mari; Nakamura, Ishin; Murahashi,Shun-Ichi. Copper(I)-Catalyzed Amination of Propargyl Esters. SelectiveSynthesis of Propargylamines, 1-Alken-3-ylamines, and (Z)-Allylamines.J. Org. Chem. (1994), 59(9), 2282-4.

To 1.17 ml (12 mmol) ethylaminoethanol in 8 ml THF were added 29.8 mg(0.3 mmol) CuCl, followed by 1 g (6.02 mmol) 1-ethynylcyclohexylacetate. The solution was stirred at RT for 3 h, the solvent was removedand the residue dissolved in ether/2M HCl. The phases were separated,and after addition of NaOH (pH 1) to the aqueous phase, it was extractedwith ether. The ether phase was dried over Na₂SO₄ and concentrated.Distillation by Kugelrohr yielded2-[Ethyl-(1-ethynyl-cyclohexyl)-amino]-ethanol as colorless oil, MS: 196(MH⁺).

37.7

In analogy to example 37.5 and 37.6, 3-Butyn-2-ol and2-Ethylaminoethanol were converted to yield2-[Ethyl-(1-methyl-prop-2-ynyl)-amino]-ethanol as colorless oil, MS: 141(M).

37.8

In analogy to example 37.5 and 37.6, 3-Butyn-2-ol andN-(Methoxyethyl)methylamine were converted to yield(2-Methoxy-ethyl)-methyl-(1-methyl-prop-2-ynyl)-amine as colorless oil,MS: 141 (M).

37.9

In analogy to example 37.5 and 37.6, 3-Butyn-2-ol andN-(Methoxyethyl)ethylamine were converted to yieldEthyl-(2-methoxy-ethyl)-(1-methyl-prop-2-ynyl)-amine as colorless oil,MS: 155 (M).

37.10

In analogy to example 37.5 and 37.6, 1-Ethinylcyclopentanol andN-Methyl-allylamine were converted to yieldAllyl-(1-ethynyl-cyclopentyl)-methyl-amine as colorless oil, MS: 163(M).

Example 38

38.1

In analogy to example 14.1, Trifluoro-methanesulfonic acid3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester andAllyl-(1,1-dimethyl-prop-2-ynyl)-methyl-amine were converted to yieldAllyl-{1,1-dimethyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-methyl-amineas brown oil, MS: 415 (MH⁺).

38.2

In analogy to example 14.1, Trifluoro-methanesulfonic acid3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and2-[(1,1-Dimethyl-prop-2-ynyl)-ethyl-amino]-ethanol were converted toyield2-((1,1-Dimethyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl)-ethyl-amino)-ethanolas off-white foam, MS: 433 (MH⁺).

38.3

In analogy to example 14.1, Trifluoro-methanesulfonic acid3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and(1,1-Dimethyl-prop-2-ynyl)-(2-methoxy-ethyl)-methyl-amine were convertedto yield{1,1-Dimethyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-(2-methoxy-ethyl)-methyl-amineas brown oil, MS: 433 (MH⁺).

38.4

In analogy to example 14.1, Trifluoro-methanesulfonic acid3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and(1,1-Dimethyl-prop-2-ynyl)-ethyl-(2-methoxy-ethyl)-amine were convertedto yield{1,1-Dimethyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-ethyl-(2-methoxy-ethyl)-amineas brown oil, MS: 447 (MH⁺).

38.5

In analogy to example 14.1, Trifluoro-methanesulfonic acid3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and2-[Ethyl-(1-ethynyl-cyclohexyl)-amino]-ethanol were converted to yield2-(Ethyl-{1-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-ylethynyl]-cyclohexyl}-amino)-ethanolas brown oil, MS: 473.3 (MH⁺).

38.6

In analogy to example 14.1, Trifluoro-methanesulfonic acid3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and2-[Ethyl-(1-methyl-prop-2-ynyl)-amino]-ethanol were converted to yield2-(Ethyl-{1-methyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amino)-ethanolas brown oil, MS: 419 (MH⁺).

38.7

In analogy to example 14.1, Trifluoro-methanesulfonic acid3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and(2-Methoxy-ethyl)-methyl-(1-methyl-prop-2-ynyl)-amine were converted toyield(2-Methoxy-ethyl)-methyl-{1-methyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amineas brown oil, MS: 419 (MH⁺).

38.8

In analogy to example 14.1, Trifluoro-methanesulfonic acid3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester andEthyl-(2-methoxy-ethyl)-(1-methyl-prop-2-ynyl)-amine were converted toyieldEthyl-(2-methoxy-ethyl)-{1-methyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amineas brown oil, MS: 433 (MH⁺).

38.9

In analogy to example 14.1, Trifluoro-methanesulfonic acid3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester andAllyl-(1-ethynyl-cyclopentyl)-methyl-amine were converted to yieldAllyl-methyl-{1-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-ylethynyl]-cyclopentyl}-amineas light yellow oil, MS: 441 (MH⁺).

Example 39

39.1

To 540 mg (11.37 mmol)2-(Ethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanolin 6 ml CH₂Cl₂ were added 0.22 ml (1.7 mmol) DAST at −78° C. Afterstirring at that temperature for 3.5 h, additional 0.2 ml (1.6 mmol)DAST were added and the mixture was slowly warmed to RT over night. Thesolution was added to a cooled aqueous solution of Na₂CO₃ and extractedwith EtOAc. The organic phase was washed with brine and dried overNa₂SO₄. Column chromatography CH₂Cl₂:MeOH 95:5 yielded 79.3 mg (16%)Ethyl-(2-fluoro-ethyl)-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amineas brown oil, MS: 441 (MH⁺).

39.2

In analogy to example 39.1,2-({4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanolwas converted to yield{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-(2-fluoro-ethyl)-amineas light yellow oil, MS: 451 (MH⁺, 1Br).

Example 40

40.1

200 mg (0.54 mmol)4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-2-methyl-but-3-yn-2-ol in2 ml THF were treated with 36 μl (5.6 mmol) 1.6 M N-Butyllithium inhexane at −78° C. for 30 min. 112 μl (0.81 mmol, 1.5 eq) Triethylaminein 0.5 ml THF and 117 μl (0.8 mmol, 1.5 eq) Diethylchlorophosphate in0.5 ml THF were added and the solution was stirred at −78° C. over nightand at 0° C. for 4 h. Water was added, and the inorganic phase wasextracted with EtOAc, the combined organic phases were washed with brineand dried over Na₂SO₄. Column chromatography on silica gel withhexane:EtOAc 3:1 gave 90 mg (33%) Phosphoric acid3-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-1,1-dimethyl-prop-2-ynylester diethyl ester as yellow semisolid, MS: 508 (MH⁺, 1Br).

40.2

To 45 mg (0.09 mmol) Phosphoric acid3-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-1,1-dimethyl-prop-2-ynylester diethyl ester and 16 μl (0.18 mmol) 2-Ethylaminoethanol in 0.5 mlTHF 10.2 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium was addedand the suspension stirred at 50° C. over night. The mixture was addedto a saturated aqueous solution of NaHCO₃ and EtOAc, the phases wereseparated and the inorganic one was extracted with EtOAc. The combinedorganic phases were washed with brine and dried over Na₂SO₄. Columnchromatography on silica gel with CH₂Cl₂:MeOH 95:5 gave2-((3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-1,1-dimethyl-prop-2-ynyl)-ethyl-amino)-ethanolas yellow semisolid, MS: 443 (MH⁺, 1Br).

Example 41

41.1

Under argon a flask was charged with 1.3 g (2.9 mmol)2-({4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amino)-ethanolin 10 ml piperidine and 170 mg (0.14 mmol, 0.05 eq) Pd(PPh₃)₄ and 28 mg(0.14 mmol, 0.05 eq) CuI. After stirring for 10 min, 1 ml (4.44 mmol,1.5 eq) (triisopropylsilyl)acetylene was added over a period of 1 h tothis solution. The solution was stirred at 80° C. for 1.5 h. Thesolution was poured on ice water, acidified and the inorganic layer wasextracted with EtOAc. The combined organic phases were washed with brineand dried over Na₂SO₄.

The crude product was dissolved in 20 ml THF and treated with 3.75 ml 1MBu₄NF in THF at RT for 1 h. The solution was diluted with EtOAc and asolution of Na₂CO₃. The inorganic layer was extracted with EtOAc, thecombined organic phases were washed with brine and dried over Na₂SO₄.Column chromatography on silica with CH₂Cl₂:MeOH 9:1 yielded 160 mg(19%)2-(Ethyl-{4-[3-(4-ethynyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanolas brown oil, MS: 395 (MH⁺).

41.2

150 mg (0.4 mmol)2-(Ethyl-{4-[3-(4-ethynyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanolin 6 ml EtOAc were hydrogenated in the presence of 50 mg 10% Pd/C,filtration over decalite, followed by purification by preparative HPLCyielded2-(Ethyl-{4-[3-(4-ethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amino)-ethanolas light yellow oil, MS: 399 (MH⁺).

Example 42

42.1

To a suspension of 0.74 g (16.9 mmol) NaH (55% in mineral oil) in 40 mlTHF was added a solution of 4 g (13.1 mmol)3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-ol in 20 ml THF at RT. Thesolution was stirred at RT for 1 h, 2.1 ml (14.3 mmol) t-butylbromoacetate was added. The solution was stirred at RT over night, 1MKHSO₄ was added carefully and the layers separated. The inorganic onewas extracted with EtOAc, the combined organic phases were washed withwater and brine and dried over Na₂SO₄. Column chromatography on silicagel with EtOAc:hexane 1:4 yielded 4.95 g (90%)[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-acetic acid tert-butylester as colorless oil, MS: 420 (MH⁺, 1Br).

42.2

3.89 g (9.3 mmol) [3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-aceticacid tert-butyl ester in 35 ml CH₂Cl₂ were added 17 ml TFA at 0° C. Thesolution was stirred at RT for 2 h, concentrated and triturated withether to yield 3 g (89%)[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-acetic acid as whitesolid, MS: 362 (M−H, 1Br).

42.3

To 400 mg (1.1 mmol)trans-5-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexyl]-pentanoic acidin 10 ml CH₂Cl₂ were added 0.82 ml (1.6 mmol, 1.5 eq) 1M dimethylaminein THF and 0.18 ml (1.6 mmol, 1.5 eq) NMM. The solution was cooled to 0°C. and 274 mg (1.43 mmol, 1.3 eq) EDCI and 30 mg (0.2 mmol) HOBT wereadded. The mixture was stirred at RT over night, partitioned betweenCH₂Cl₂ and a saturated aqueous solution of NaHCO₃. The organic phase waswashed with KHSO₄ and brine, dried over Na₂SO₄ and evaporated. Columnchromatography with EtOAc/hexane 2:1 gave 370 mg (86%)2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-N,N-dimethyl-acetamideas white solid, mp 168° C., MS: 391 (MH⁺, 1Br).

42.4

Analogously to example 42.3, from[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-acetic acid andN,O-Dimethylhydroxylamine hydrochloride was prepared2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-N-methoxy-N-methyl-acetamideas white solid, mp 159° C., MS: 407 (MH⁺, 1Br).

42.5

To a solution of 160 mg (0.41 mmol)2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-N,N-dimethyl-acetamidein 4 ml THF was added 95 mg (4.1 mmol, 1 eq) zirconium(IV) chloride at−10° C. and the reaction mixture was stirred for additional 30 min. 0.82ml 3M (24.5 mmol, 6 eq) methylmagnesium bromide in THF were added at−10° C. and the mixture was warmed to RT. After stirring for 1 h, themixture was added to a mixture of 30% NaOH and CH₂Cl₂. The inorganicphase was extracted with CH₂Cl₂ and the combined organic phases werewashed with brine and dried over Na₂SO₄ and evaporated. The residue waspurified by column chromatography on silica gel with CH₂Cl₂ toCH₂Cl₂:MeOH 9:1 to yield 63 mg (38%){2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-1,1-dimethyl-ethyl}-dimethyl-amineas colorless oil, MS: 405 (MH⁺, 1Br).

42.6

To 208 mg (0.51 mmol)2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-N-methoxy-N-methyl-acetamidein 8 ml THF were added 0.51 ml 3M (1.53 mmol, 3 eq)methylmagnesiumbromide in THF at −75° C. The solution was slowly warmedto RT over night, a saturated aqueous solution of NH₄Cl was added andthe mixture stirred for 30 min. The phases were separated and theinorganic phase was extracted with EtOAc. The combined organic phaseswere dried over Na₂SO₄ and evaporated. Column chromatography on silicagel with EtOAc:hexane 1:4 yielded 109 mg (53%)1-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propan-2-one as whitesolid, MS: 361 (M, 1Br).

42.7

74 mg (0.20 mmol)1-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propan-2-one weretreated with 133 μM 2M (0.17 mmol) dimethylamine in THF and 60 μM (0.20mmol) tetraisopropyl orthotitanate. The solution was stirred at RT for3.5 h. The mixture was diluted with 2 ml ethanol and 15 mg (0.2 mmol)NaCNBH₃ were added, and stirring was continued over night. NaHCO₃ andEtOAc were added, the inorganic phase extracted with EtOAc. The organicphases were washed with water and brine, dried over Na₂SO₄ andevaporated. Column chromatography with CH₂Cl₂:MeOH 9:1 gave{2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-1-methyl-ethyl}-dimethyl-amineas colorless oil, MS: 391 (MH⁺, 1Br).

Example 43

43.1

In analogy to example 12.1,2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-ol (example26.5) was treated with trifluoromethane sulfonic anhydride in pyridineto yield the Trifluoro-methanesulfonic acid2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl ester aslight brown oil, MS: 440 (M⁺).

43.2

In analogy to example 12.1, 3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-oland trifluoromethane sulfonic anhydride were converted to yieldTrifluoro-methanesulfonic acid3-(4-fluoro-phenyl)-benzo[b]thiophene-6-yl ester as brown oil, MS: 376(M).

Example 44

44.1

In analogy to example 13.1, the Trifluoro-methanesulfonic acid2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl ester wasreacted with 2-propyn-1-ol to yield the3-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-prop-2-yn-1-olas yellow oil, MS: 346 (M⁺).

44.2

In analogy to example 13.1, the Trifluoro-methanesulfonic acid2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl ester wasreacted with 3-butyn-1-ol to yield the4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-but-3-yn-1-olas brown oil, MS: 360 (M⁺).

44.3

In analogy to example 13.1, the Trifluoro-methanesulfonic acid2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl ester wasreacted with 4-pentyn-1-ol to yield the5-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-olas brown oil, MS: 374 (M⁺).

44.4

In analogy to example 14.1, Trifluoro-methanesulfonic acid3-(4-fluoro-phenyl)-benzo[b]thiophene-6-yl ester and 4-pentyn-1-ol wereconverted to yield5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol as lightgreen solid, MS: 310 (M).

Example 45

45.1

In analogy to example 20.1, the3-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-prop-2-yn-1-olwas hydrogenated to yield the3-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-propan-1-olas colorless oil, MS: 350 (M⁺).

45.2

In analogy to example 20.1, the4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-but-3-yn-1-olwas hydrogenated to yield the4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-butan-1-olas yellowish oil, MS: 364 (M⁺).

Example 46

46.1

In analogy to example 21.1, the3-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-propan-1-olwas treated with methanesulfonic acid chloride to yield theMethanesulfonic acid3-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-propylester as yellow oil, MS: 428 (M⁺).

46.2

In analogy to example 21.1, the4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-butan-1-olwas treated with methanesulfonic acid chloride to yield theMethanesulfonic acid4-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-butylester as yellowish oil, MS: 442 (M⁺).

46.3

In analogy to example 21.1, the5-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-olwas treated with methanesulfonic acid chloride to yield theMethanesulfonic acid5-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynylester as yellow oil, MS: 452 (M⁺).

46.4

In analogy to example 21.1, the3-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-prop-2-yn-1-olwas treated with methanesulfonic acid chloride to yield a mixture of theMethanesulfonic acid3-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-prop-2-ynylester and the6-(3-Chloro-prop-1-ynyl)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiopheneas yellow oil, used without further characterization.

Example 47

47.1

In analogy to example 32.1, the Methanesulfonic acid3-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-propylester was converted to yield the Methanesulfonic acid3-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l6-benzo[b]thiophen-6-yl]-propyl ester as yellow oil, MS: 478 (MNH₄ ⁺).

47.2

In analogy to example 32.1, the Methanesulfonic acid4-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-butylester was converted to yield the Methanesulfonic acid4-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l6-benzo[b]thiophen-6-yl]-butyl ester as yellowish oil, MS: 474 (M⁺).

47.3

In analogy to example 32.1, the Methanesulfonic acid5-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynylester was converted to yield the Methanesulfonic acid5-[2-methyl-1,1-dioxo-3-(4-trifluoromethyl-phenyl)-1H-1l6-benzo[b]thiophen-6-yl]-pent-4-ynyl ester as colorless foam, MS: 484(M⁺).

Example 48

In analogy to the method described in example 33, Methanesulfonic acidesters or Chlorides were treated with secondary or primary amines inN,N-dimethylacetamide between room temperature and 60° C. to yieldtertiary or secondary amine products as listed in the following table.The compounds were obtained as colorless, yellowish or brown oils.

MS Methanesulfonate/ Example Compound MH⁺ Chloride Amine 48.1Methyl-{3-[2-methyl-3- 402 mixture of the Methanesulfonic N-methyl-(4-trifluoromethyl- acid 3-[2-methyl-3-(4- propylamine phenyl)-trifluoromethyl-phenyl)- benzo[b]thiophen-6-yl]-benzo[b]thiophen-6-yl]-prop-2- prop-2-ynyl}-propyl- ynyl ester and the6-(3-Chloro- amine prop-1-ynyl)-2-methyl-3-(4- trifluoromethyl-phenyl)-benzo[b]thiophene 48.2 2-(Ethyl-{3-[2-methyl-3- 418 mixture of theMethanesulfonic 2-ethylamino- (4-trifluoromethyl- acid 3-[2-methyl-3-(4-ethanol phenyl)- trifluoromethyl-phenyl)- benzo[b]thiophen-6-yl]-benzo[b]thiophen-6-yl]-prop-2- prop-2-ynyl}-amino)- ynyl ester and the6-(3-Chloro- ethanol prop-1-ynyl)-2-methyl-3-(4-trifluoromethyl-phenyl)- benzo[b]thiophene 48.3 Diethyl-{3-[2-methyl-3-402 mixture of the Methanesulfonic diethyl-amine (4-trifluoromethyl-acid 3-[2-methyl-3-(4- phenyl)- trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]- benzo[b]thiophen-6-yl]-prop-2-prop-2-ynyl}-amine ynyl ester and the 6-(3-Chloro-prop-1-ynyl)-2-methyl-3-(4- trifluoromethyl-phenyl)- benzo[b]thiophene48.4 Allyl-methyl-{3-[2- 400 mixture of the Methanesulfonic N-allyl-methyl-3-(4- acid 3-[2-methyl-3-(4- methyl-aminetrifluoromethyl-phenyl)- trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]- benzo[b]thiophen-6-yl]-prop-2-prop-2-ynyl}-amine ynyl ester and the 6-(3-Chloro-prop-1-ynyl)-2-methyl-3-(4- trifluoromethyl-phenyl)- benzo[b]thiophene48.5 Allyl-methyl-{5-[2- 428 Methanesulfonic acid 5-[2- N-allyl-methyl-3-(4- methyl-3-(4-trifluoromethyl- methyl-aminetrifluoromethyl-phenyl)- phenyl)-benzo[b]thiophen-6-benzo[b]thiophen-6-yl]- yl]-pent-4-ynyl ester pent-4-ynyl}-amine 48.6Methyl-{5-[2-methyl-3- 430 Methanesulfonic acid 5-[2- N-methyl-(4-trifluoromethyl- methyl-3-(4-trifluoromethyl- propyl-amine phenyl)-phenyl)-benzo[b]thiophen-6- benzo[b]thiophen-6-yl]- yl]-pent-4-ynylester pent-4-ynyl}-propyl- amine 48.7 2-(Ethyl-{5-[2-methyl-3- 446Methanesulfonic acid 5-[2- 2-ethylamino- (4-trifluoromethyl-methyl-3-(4-trifluoromethyl- ethanol phenyl)-phenyl)-benzo[b]thiophen-6- benzo[b]thiophen-6-yl]- yl]-pent-4-ynylester pent-4-ynyl}-amino)- ethanol 48.8 Diethyl-{5-[2-methyl-3- 430Methanesulfonic acid 5-[2- diethyl-amine (4-trifluoromethyl-methyl-3-(4-trifluoromethyl- phenyl)- phenyl)-benzo[b]thiophen-6-benzo[b]thiophen-6-yl]- yl]-pent-4-ynyl ester pent-4-ynyl}-amine 48.91-{3-[2-Methyl-3-(4- 390 Methanesulfonic acid 3-[2- azetidinetrifluoromethyl-phenyl)- methyl-3-(4-trifluoromethyl-benzo[b]thiophen-6-yl]- phenyl)-benzo[b]thiophen-6- propyl}-azetidineyl]-propyl ester 48.10 1-{3-[2-Methyl-3-(4- 434 Methanesulfonic acid3-[2- 4-hydroxy- trifluoromethyl-phenyl)- methyl-3-(4-trifluoromethyl-piperidine benzo[b]thiophen-6-yl]- phenyl)-benzo[b]thiophen-6-propyl}-piperidin-4-ol yl]-propyl ester 48.11 1-{3-[2-Methyl-3-(4- 418Methanesulfonic acid 3-[2- piperidine trifluoromethyl-phenyl)-methyl-3-(4-trifluoromethyl- benzo[b]thiophen-6-yl]-phenyl)-benzo[b]thiophen-6- propyl}-piperidine yl]-propyl ester 48.121-{3-[2-Methyl-3-(4- 404 Methanesulfonic acid 3-[2- pyrrolidinetrifluoromethyl-phenyl)- methyl-3-(4-trifluoromethyl-benzo[b]thiophen-6-yl]- phenyl)-benzo[b]thiophen-6- propyl}-pyrrolidineyl]-propyl ester 48.13 2-(Ethyl-{3-[2-methyl-3- 422 Methanesulfonic acid3-[2- 2-ethylamino- (4-trifluoromethyl- methyl-3-(4-trifluoromethyl-ethanol phenyl)- phenyl)-benzo[b]thiophen-6- benzo[b]thiophen-6-yl]-yl]-propyl ester propyl}-amino)-ethanol 48.14 Allyl-methyl-{3-[2- 404Methanesulfonic acid 3-[2- N-allyl- methyl-3-(4-methyl-3-(4-trifluoromethyl- methylamine trifluoromethyl-phenyl)-phenyl)-benzo[b]thiophen-6- benzo[b]thiophen-6-yl]- yl]-propyl esterpropyl}-amine 48.15 Allyl-methyl-{4-[2- 418 Methanesulfonic acid 4-[2-N-allyl- methyl-3-(4- methyl-3-(4-trifluoromethyl- methylaminetrifluoromethyl-phenyl)- phenyl)-benzo[b]thiophen-6-benzo[b]thiophen-6-yl]- yl]-butyl ester butyl}-amine 48.162-(Ethyl-{4-[2-methyl-3- 436 Methanesulfonic acid 4-[2- 2-ethylamino-(4-trifluoromethyl- methyl-3-(4-trifluoromethyl- ethanol phenyl)-phenyl)-benzo[b]thiophen-6- benzo[b]thiophen-6-yl]- yl]-butyl esterbutyl}-amino)-ethanol 48.17 2-{4-[2-Methyl-3-(4- 408 Methanesulfonicacid 4-[2- ethanolamine trifluoromethyl-phenyl)-methyl-3-(4-trifluoromethyl- benzo[b]thiophen-6-yl]-phenyl)-benzo[b]thiophen-6- butylamino}-ethanol yl]-butyl ester 48.181-{4-[2-Methyl-3-(4- 432 Methanesulfonic acid 4-[2- piperidinetrifluoromethyl-phenyl)- methyl-3-(4-trifluoromethyl-benzo[b]thiophen-6-yl]- phenyl)-benzo[b]thiophen-6- butyl}-piperidineyl]-butyl ester 48.19 1-{4-[2-Methyl-3-(4- 448 Methanesulfonic acid4-[2- 4-hydroxy- trifluoromethyl-phenyl)- methyl-3-(4-trifluoromethyl-piperidine benzo[b]thiophen-6-yl]- phenyl)-benzo[b]thiophen-6-butyl}-piperidin-4-ol yl]-butyl ester 48.20 {4-[2-Methyl-3-(4- 406Methanesulfonic acid 4-[2- propylamine trifluoromethyl-phenyl)-methyl-3-(4-trifluoromethyl- benzo[b]thiophen-6-yl]-phenyl)-benzo[b]thiophen-6- butyl}-propyl-amine yl]-butyl ester 48.212-(Ethyl-{3-[2-methyl- 454 Methanesulfonic acid 3-[2- 2-ethylamino-1,1-dioxo-3-(4-trifluoromethyl- methyl-1,1-dioxo-3-(4- ethanolphenyl)-1H-1l 6- trifluoromethyl-phenyl)-1H-1l benzo[b]thiophen-6-yl]-6-benzo[b]thiophen-6-yl]- propyl}-amino)-ethanol propyl ester 48.222-{3-[2-Methyl-1,1- 426 Methanesulfonic acid 3-[2- ethanolaminedioxo-3-(4-trifluoromethyl- methyl-1,1-dioxo-3-(4- phenyl)-1H-1l 6-trifluoromethyl-phenyl)-1H-1l benzo[b]thiophen-6-yl]-6-benzo[b]thiophen-6-yl]- propylamino}-ethanol propyl ester 48.23{3-[2-Methyl-1,1-dioxo- 424 Methanesulfonic acid 3-[2- N-propyl-3-(4-trifluoromethyl- methyl-1,1-dioxo-3-(4- amine phenyl)-1H-1l 6-trifluoromethyl-phenyl)-1H-1l benzo[b]thiophen-6-yl]-6-benzo[b]thiophen-6-yl]- propyl]-propyl-amine propyl ester 48.241-{3-[2-Methyl-1,1- 466 Methanesulfonic acid 3-[2- 4-hydroxy-dioxo-3-(4-trifluoromethyl- methyl-1,1-dioxo-3-(4- piperidinephenyl)-1H-1l 6- trifluoromethyl-phenyl)-1H-1l benzo[b]thiophen-6-yl]-6-benzo[b]thiophen-6-yl]- propyl}-piperidin-4-ol propyl ester 48.251-{3-[2-Methyl-1,1- 450 Methanesulfonic acid 3-[2- piperidinedioxo-3-(4-trifluoro- methyl-1,1-dioxo-3-(4- methyl-phenyl)-1H-1l 6-trifluoromethyl-phenyl)-1H-1l benzo[b]thiophen-6-yl]-6-benzo[b]thiophen-6-yl]- propyl}-piperidine propyl ester 48.26Allyl-methyl-{3-[2- 436 Methanesulfonic acid 3-[2- N-allyl-methyl-1,1-dioxo-3-(4- methyl-1,1-dioxo-3-(4- methylaminetrifluoromethyl-phenyl)- trifluoromethyl-phenyl)-1H-1l 1H-1l 6-6-benzo[b]thiophen-6-yl]- benzo[b]thiophen-6-yl]- propyl esterpropyl}-amine 48.27 2-(Ethyl-{4-[2-methyl- 468 Methanesulfonic acid4-[2- 2-ethylamino- 1,1-dioxo-3-(4-trifluoro- methyl-1,1-dioxo-3-(4-ethanol methyl-phenyl)-1H-1l 6- trifluoromethyl-phenyl)-1H-1lbenzo[b]thiophen-6-yl]- 6-benzo[b]thiophen-6-yl]-butylbutyl}-amino)-ethanol ester 48.28 Allyl-methyl-{4-[2- 450Methanesulfonic acid 4-[2- N-allyl- methyl-1,1-dioxo-3-(4-methyl-1,1-dioxo-3-(4- methylamine trifluoromethyl-phenyl)-trifluoromethyl-phenyl)-1H-1l 1H-1l 6- 6-benzo[b]thiophen-6-yl]-butylbenzo[b]thiophen-6-yl]- ester butyl}-amine 48.29 1-{4-[2-Methyl-1,1- 464Methanesulfonic acid 4-[2- piperidine dioxo-3-(4-trifluoro-methyl-1,1-dioxo-3-(4- methyl-phenyl)-1H-1l 6-trifluoromethyl-phenyl)-1H-1l benzo[b]thiophen-6-yl]-6-benzo[b]thiophen-6-yl]-butyl butyl}-piperidine ester 48.301-{4-[2-Methyl-1,1- 480 Methanesulfonic acid 4-[2- 4-hydroxy-dioxo-3-(4-trifluoro- methyl-1,1-dioxo-3-(4- piperidinemethyl-phenyl)-1H-1l 6- trifluoromethyl-phenyl)-1H-1lbenzo[b]thiophen-6-yl]- 6-benzo[b]thiophen-6-yl]-butylbutyl}-piperidin-4-ol ester 48.31 {4-[2-Methyl-1,1-dioxo- 438Methanesulfonic acid 4-[2- N-propyl- 3-(4-trifluoromethyl-methyl-1,1-dioxo-3-(4- amine phenyl)-1H-1l 6-trifluoromethyl-phenyl)-1H-1l benzo[b]thiophen-6-yl]-6-benzo[b]thiophen-6-yl]-butyl butyl}-propyl-amine ester 48.322-{4-[2-Methyl-1,1- 440 Methanesulfonic acid 4-[2- ethanolaminedioxo-3-(4-trifluoro- methyl-1,1-dioxo-3-(4- methyl-phenyl)-1H-1l 6-trifluoromethyl-phenyl)-1H-1l benzo[b]thiophen-6-yl]-6-benzo[b]thiophen-6-yl]-butyl butylamino}-ethanol ester 48.332-(Ethyl-{5-[2-methyl- 478 Methanesulfonic acid 5-[2- 2-ethylamino-1,1-dioxo-3-(4-trifluoro- methyl-1,1-dioxo-3-(4- ethanolmethyl-phenyl)-1H-1l 6- trifluoromethyl-phenyl)-1H-1lbenzo[b]thiophen-6-yl]- 6-benzo[b]thiophen-6-yl]-pent-pent-4-ynyl}-amino)- 4-ynyl ester ethanol 48.34 Methyl-{5-[2-methyl-1,1-462 Methanesulfonic acid 5-[2- N-methyl- dioxo-3-(4-trifluoro-methyl-1,1-dioxo-3-(4- propylamine methyl-phenyl)-1H-1l 6-trifluoromethyl-phenyl)-1H-1l benzo[b]thiophen-6-yl]-6-benzo[b]thiophen-6-yl]-pent- pent-4-ynyl}-propyl- 4-ynyl ester amine48.35 Allyl-methyl-{5-[2- 460 Methanesulfonic acid 5-[2- N-allyl-methyl-1,1-dioxo-3-(4- methyl-1,1-dioxo-3-(4- methylaminetrifluoromethyl-phenyl)- trifluoromethyl-phenyl)-1H-1l 1H-1l 6-6-benzo[b]thiophen-6-yl]-pent- benzo[b]thiophen-6-yl]- 4-ynyl esterpent-4-ynyl}-amine 48.36 Diethyl-{5-[2-methyl- 462 Methanesulfonic acid5-[2- diethyl-amine 1,1-dioxo-3-(4-trifluoro- methyl-1,1-dioxo-3-(4-methyl-phenyl)-1H-1l 6- trifluoromethyl-phenyl)-1H-1lbenzo[b]thiophen-6-yl]- 6-benzo[b]thiophen-6-yl]-pent-pent-4-ynyl}-amine 4-ynyl ester

Example 49

49.1

In analogy to example 19.1,5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol and2-(Methylamino)ethanol were converted to yield2-({5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-methyl-amino)-ethanolas light brown oil, MS: 368 (MH⁺).

49.2

In analogy to example 19.1,5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol and2-(Ethylamino)ethanol were converted to yield2-(Ethyl-{5-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-amino)-ethanolas light brown oil, MS: 382 (MH⁺).

49.3

RO0721678-000: In analogy to example 19.1,5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol andDimethylamine were converted to yield{5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-dimethyl-amineas light brown semisolid, MS: 338 (MH⁺).

49.4

In analogy to example 19.1,5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol andN-Allylmethylamine were converted to yieldAllyl-{5-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-methyl-amineas brown oil, MS: 364 (MH⁺).

49.5

In analogy to example 19.1,5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol andN-(Methoxyethyl)ethylamine were converted to yieldEthyl-{5-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-(2-methoxy-ethyl)-amineas light brown oil, MS: 396 (MH⁺).

49.6

In analogy to example 19.1,5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol andN-(Methoxyethyl)methylamine CH₂Cl₂. were converted to yield{5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-ynyl}-(2-methoxy-ethyl)-methyl-amineas brown oil, MS: 382 (MH⁺).

49.7

In analogy to example 19.1,4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butan-1-ol andN-Methylallylamine were converted to yieldAllyl-{4-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-methyl-amineas colorless oil, MS: 415 (MH⁺, 1Br).

49.8

In analogy to example 19.1,4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butan-1-ol andDimethylamine were converted to yield{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-dimethyl-amine asbrown oil, MS: 389 (MH⁺, 1Br).

49.9

In analogy to example 19.1,4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butan-1-ol and2-(Methylamino)ethanol were converted to yield2-({4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-methyl-amino)-ethanolas brown oil, MS: 419 (MH⁺, 1Br).

49.10

In analogy to example 19.1,4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butan-1-ol and2-(Ethylamino)ethanol were converted to yield2-({4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-ethyl-amino)-ethanolas yellow oil, MS: 433 (MH⁺, 1Br).

49.11

In analogy to example 19.1,4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butan-1-ol andN-(Methoxyethyl)ethylamine were converted to yield{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-ethyl-(2-methoxy-ethyl)-amineas yellow oil, MS: 447 (MH⁺, 1Br).

49.12

In analogy to example 19.1,4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butan-1-ol andN-(Methoxyethyl)methylamine were converted to yield{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-(2-methoxy-ethyl)-methyl-amineas yellow oil, MS: 433 (MH⁺, 1Br).

Example 50

50.1

4.0 g (13.0 mmol)2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-ol (example26.5) dissolved in 30 ml N,N-dimethylformamide were treated with 2.69 g(19.5 mmol, 1.5 eq) K₂CO₃ and 3.06 ml (19.5 mmol, 1.5 eq)2-(2-Bromo-ethoxy)-tetrahydro-pyran. The reaction mixture was stirred at120° C. for 3 hours, cooled to room temperature, poured into 100 ml ofice-water and extracted 3 times with 50 ml of ether. The combined etherphases were washed with brine, dried over magnesium sulfate andevaporated under reduced pressure. The residue formed was filtered oversilica gel with dichloromethane as the eluent giving 5.76 g crude2-{2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethoxy}-tetrahydro-pyran.This crude product was subsequently dissolved in 70 ml of 2N HCl inmethanol and the reaction mixture stirred for 1 hour at roomtemperature. Subsequently, it was poured into a diluted sodiumhydroxide/ice solution and extracted 3 times with 150 ml ofdichloromethane. The combined dichloromethane phases were washed withbrine, dried over magnesium sulfate and evaporated under reducedpressure. The residue formed was chromatographed on silica gel withdichloromethane as the eluent giving 4.3 g (93%)2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethanolas colorless solid, MS: 352 (M⁺).

50.2

In analogy to example 21.1,2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethanoland methanesulfonic acid chloride were converted to yieldMethanesulfonic acid2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethylester as colorless solid, MS: 430 (M⁺).

50.3

0.300 g (0.697 mmol) Methanesulfonic acid2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethylester dissolved in 2.0 ml of N,N-dimethylformamide were treated with0.137 g (2.09 mmol) sodium azide and the reaction mixture heated to 80°C. for 1 hour. It was then cooled to room temperature, poured into 30 mlof ice-water and extracted 3 times with 10 ml of ether. The combinedether phases were washed with brine, dried over magnesium sulfate andevaporated under reduced pressure giving 0.262 g (99.6%)6-(2-Azido-ethoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiopheneas colorless oil, MS: 377 (M⁺).

50.4

0.230 g (0.610 mmol)6-(2-Azido-ethoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiopheneand 0.484 g (1.83 mmol) of triphenylphosphin were dissolved in 1.6 ml oftetrahydrofuran. After stirring of the reaction mixture for 15 minutesat room temperature, 0.1 ml of water were added and the reaction mixtureheated to 60° C. for 16 hours. It was then evaporated under reducedpressure, poured into 50 ml of water and extracted 3 times with 10 ml ofdichloromethane. The combined dichloromethane phases were washed withbrine, dried over magnesium sulfate and evaporated under reducedpressure. The residue formed was chromatographed on silica gel with a9:1 v/v mixture of dichloromethane and methanol as the eluent giving0.200 g (93.4%)2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethylamineas colorless oil, MS: 352 (MH⁺).

50.5

In analogy to the procedures described in examples 49.3 and 49.4,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene(example 27.5) was reacted with sodium azide to yield6-(4-Azido-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene, whichwas further reduced with triphenylphosphin and water to yield4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butylamine ascolorless oil, MS: 390 (MH⁺, 1Br).

Example 51

51.1

In analogy to the method described in example 17.1, Methanesulfonic acid2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethylester (example 50.2) was treated with methylamine in ethanol andN,N-dimethylacetamide to yieldMethyl-{2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-amineas colorless oil, MS: 366 (MH⁺).

51.2

In analogy to the method described in example 17.1,6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene(example 27.5) was treated with methylamine in ethanol andN,N-dimethylacetamide to yield{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amineas colorless oil, MS: 405 (MH⁺).

Example 52

52.1

A solution of 40 mg (0.109 mmol)Methyl-{2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-amine(example 51.1), 0.0211 g (0.164 mmol) of 4-chloro-2-methyl-pyrimidine[Ger. Offen. (1990), DE3905364 A1] and 0.038 ml (0.22 mmol)N-ethyl-diisopropylamine in 1 ml of N,N-dimethylformamide was stirredfor 2 hours at 80° C. The reaction mixture was then cooled to roomtemperature, poured into 30 ml of ice-water and extracted 3 times with10 ml of ether. The combined ether phases were washed with brine, driedover magnesium sulfate and evaporated under reduced pressure. Theresidue formed was chromatographed on silica gel with a 95:5:1 v/v/vmixture of dichloromethane, methanol and saturated aqueous ammonia asthe eluent giving 37.3 mg (74.5%)Methyl-(2-methyl-pyrimidin-4-yl)-{2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-amineas light brown solid, MS: 458 (MH⁺).

In analogy to the method described in example 52.1, primary or secondaryamines were reacted with halo-heterocyclic compounds inN,N-dimethylformamide to yield products as listed in the followingtable. The compounds were obtained as colorless or light brown oils orsolids.

MS Primary or Secondary Example Product MH⁺ Amine Halo-Heterocycle 52.2Methyl-{2-[2-methyl-3- 444 Methyl-{2-[2-methyl- 4-Chloro-pyrimidine(4-trifluoromethyl- 3-(4-trifluoromethyl- [PCT Int. Appl. (1998),phenyl)- phenyl)- WO9821188A1] benzo[b]thiophen-6- benzo[b]thiophen-6-yloxy]-ethyl}-pyrimidin- yloxy]-ethyl}-amine 4-yl-amine 52.3(2-Methyl-pyrimidin-4- 444 2-[2-Methyl-3-(4- 4-Chloro-2-methyl-yl)-{2-[2-methyl-3-(4- trifluoromethyl- pyrimidinetrifluoromethyl-phenyl)- phenyl)- benzo[b]thiophen-6-benzo[b]thiophen-6- yloxy]-ethyl}-amine yloxy]-ethylamine 52.4{2-[2-Methyl-3-(4- 430 2-[2-Methyl-3-(4- 4-Chloro-pyrimidinetrifluoromethyl-phenyl)- trifluoromethyl- benzo[b]thiophen-6- phenyl)-yloxy]-ethyl}-pyrimidin- benzo[b]thiophen-6- 4-yl-amineyloxy]-ethylamine 52.5 {4-[3-(4-Bromo-phenyl)- 496, {4-[3-(4-Bromo-4-Chloro-2-methyl- 2-methyl- 1Br phenyl)-2-methyl- pyrimidinebenzo[b]thiophen-6- benzo[b]thiophen-6- yloxy]-butyl}-methyl-(2-yloxy]-butyl}-methyl- methyl-pyrimidin-4-yl)- amine amine 52.6{4-[3-(4-Bromo-phenyl)- 482, {4-[3-(4-Bromo- 4-Chloro-pyrimidine2-methyl- 1Br phenyl)-2-methyl- benzo[b]thiophen-6- benzo[b]thiophen-6-yloxy]-butyl}-methyl- yloxy]-butyl}-methyl- pyrimidin-4-yl-amine amine52.7 {4-[3-(4-Bromo-phenyl)- 482, 4-[3-(4-Bromo- 4-Chloro-2-methyl-2-methyl- 1Br phenyl)-2-methyl- pyrimidine benzo[b]thiophen-6-benzo[b]thiophen-6- yloxy]-butyl}-(2-methyl- yloxy]-butylaminepyrimidin-4-yl)-amine 52.8 {4-[3-(4-Bromo-phenyl)- 468, 4-[3-(4-Bromo-4-Chloro-pyrimidine 2-methyl- 1Br phenyl)-2-methyl- benzo[b]thiophen-6-benzo[b]thiophen-6- yloxy]-butyl}-pyrimidin- yloxy]-butylamine4-yl-amine 52.9 {4-[3-(4-Bromo-phenyl)- 481 {4-[3-(4-Bromo-4-Chloro-pyridine 2-methyl- 1Br phenyl)-2-methyl- benzo[b]thiophen-6-benzo[b]thiophen-6- yloxy]-butyl}-methyl- yloxy]-butyl}-methyl-pyridin-4-yl-amine amine

Example 53

53.1

A solution of 100 mg (0.220 mmol)6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene(example 27.5), 0.024 g (0.35 mmol) of imidazole and 0.0144 g (0.330mmol) sodium hydride (55% suspension in oil) in 0.5 ml ofN,N-dimethylformamide was stirred for 1 hour at room temperature. Thereaction mixture was then poured into 30 ml of ice-water and extracted 3times with 10 ml of ether. The combined ether phases were washed withbrine, dried over magnesium sulfate and evaporated under reducedpressure. The residue formed was chromatographed on silica gel with a9:1 v/v mixture of dichloromethane and methanol as the eluent yielding84.2 mg (86.7%)1-{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-1H-imidazoleas colorless oil, MS: 441 (MH⁺, 1Br).

53.2

In analogy to the procedure described in example 53.1, Methanesulfonicacid2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethylester (example 49.2) was reacted with imidazole and sodium hydride inN,N-dimethylformamide at room temperature to yield1-{2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl}-1H-imidazoleas colorless oil, MS: 403 (MH⁺).

Example A

Tablets containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per tablet Compound of formula I 10.0-100.0 mg Lactose 125.0mg Maize starch 75.0 mg Talc 4.0 mg Magnesium stearate 1.0 mg

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula I 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc  5.0 mg

Example C

Injection solutions can have the following composition:

Compound of formula I 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Water forinjection solutions ad 1.0 ml

1. A compound selected from the group consisting of compounds of formula(I)

wherein U is a lone pair, Y is CR¹, Z is S or S(O₂), V is —CH₂—, andm+n≦2, Q is phenyl optionally substituted by 1 to 3 substituentsindependently selected from the group as defined for R³, A¹ is hydrogen,lower-alkenyl, or lower-alkyl substituted with hydroxy, lower-alkoxy, A²is cycloalkyl, cycloalkyl-lower-alkyl, lower-alkenyl, lower-alkinyl,heteroaryl, or lower-alkyl optionally substituted with halogen, hydroxy,or lower-alkoxy, or A¹ and A² are bonded to each other to form a ringand -A¹-A²- is lower-alkylene, or lower-alkenylene, optionallysubstituted by R⁴, in which one —CH₂— group of -A¹-A²- can optionally bereplaced by a NR⁵, S, or O, or -A¹-A²- is —CH═N═CH═CH— which canoptionally be substituted by lower-alkyl, A³ and A⁴ independently fromeach other are hydrogen or lower-alkyl, X is hydrogen R¹ is lower-alkyl,R³ is halogen, piperidyl, piperazinyl, piperazinyl-ethanone,morpholinyl, CONH₂, CN, NO₂, CF₃, OH, lower-alkoxy, thio-lower-alkoxy,or is lower-alkyl, lower-alkenyl, or lower-alkinyl, optionallysubstituted with OH or SH, R⁴ is hydroxy, lower-alkyl, lower-alkoxy, orthio-lower-alkoxy, R⁵ is hydrogen or lower-alkyl, pharmaceuticallyacceptable salts of compounds of formula (I); and pharmaceuticallyacceptable esters of compounds of formula (I).
 2. The compound accordingto claim 1, wherein A¹ is hydrogen, lower-alkenyl, or lower-alkylsubstituted with hydroxy or lower-alkoxy, A² is cycloalkyl,cycloalkyl-lower-alkyl, lower-alkenyl, lower-alkinyl, or lower-alkyloptionally substituted with hydroxy or lower-alkoxy, or A¹ and A² arebonded to each other to form a ring and -A¹-A²- is lower-alkylene, orlower-alkenylene, optionally substituted by R⁴, in which one —CH₂— groupof -A¹-A²- can optionally be replaced by a NR⁵, S, or O; A³ and A⁴independently from each other are hydrogen or lower-alkyl; and R³ ishalogen, NH₂, N(lower-alkyl)₂, CONH₂, CN, NO₂, CF₃, OH, lower-alkoxy,thio-lower-alkoxy, or is lower-alkyl, lower-alkenyl, or lower-alkinyl,optionally substituted with OH, SH or NH₂.
 3. The compound according toclaim 1, wherein A¹ is hydrogenor methyl, or ethyl substituted withhydroxy or methoxy.
 4. The compound according to claim 3, wherein A² ismethyl, n-propyl, i-propyl, 2-propenyl, 2-propinyl,1,1-dimethyl-2-propinyl, cyclopropyl-methylene, or ethyl optionallysubstituted with hydroxy or methoxy.
 5. The compound according to claim4, wherein A² is methyl, ethyl, 2-hydroxy-ethyl, 2-methoxy-ethyl,n-propyl, 2-propenyl, or cyclopropyl-methylene.
 6. The compoundsaccording to claim 3, wherein A² is 2-Methyl-pyrimidin-4-yl.
 7. Thecompound according to claim 1, wherein A¹ and A² are bonded to eachother to form a ring and -A¹-A²- is lower-alkylene, optionallysubstituted by R⁴, in which one —CH₂— group of -A¹-A²- can optionally bereplaced by NR⁵ or O, wherein R⁴ is hydroxy, and R⁵ is lower-alkyl orlower-alkyl-carbonyl, or -A¹-A²- is —CH═N═CH═CH—.
 8. The compoundaccording to claim 7, wherein R⁵ is methyl.
 9. The compound according toclaim 7, wherein -A¹-A²- is —(CH₂)₅—.
 10. The compound according toclaim 1, wherein A³ is hydrogen.
 11. The compound according to claim 10,wherein A⁴ is hydrogen.
 12. The compound according to claim 1, whereinA³ is methyl.
 13. The compound according to claim 10, wherein A⁴ ismethyl.
 14. The compound according to claim 1, wherein Y is CR¹ and R¹is methyl.
 15. The compound according to claim 1, wherein Z is S. 16.The compound according to claim 1, wherein Z is SO₂.
 17. The compoundaccording to claim 1, wherein Q is phenyl optionally substituted by 1 to3 substituents independently selected from the group as defined for R³,wherein R³ is fluorine, chlorine, bromine, or CF₃.
 18. The compoundaccording to claim 17, wherein Q is 4-chloro-phenyl, 4-bromo-phenyl, or4-trifluoromethyl-phenyl.
 19. A compound selected from the groupconsisting of: compounds of formula (VII)

wherein Y is CR¹, Z is S or S(O₂), V is CH₂, R³ is halogen or CF₃, m is1, 2 or 3, A¹ is hydrogen, lower-alkyl or lower-alkoxy, and A² is loweralkyl, lower alkoxy, lower alkyl-lower alkoxy, lower alkenyl,cycloalkyl, pyrimidine or pyrimidine-lower alkyl or A¹ and A² are bondedto each other to form a lower alkyl in which one —CH₂— group isoptionally replaced by a NR⁵, A³ is hydrogen or lower alkyl, A⁴ ishydrogen or lower-alkyl, R¹ is hydrogen or lower-alkyl, and R⁵ ishydrogen or lower-alkyl; pharmaceutically acceptable salts of compoundsof formula (VII); and pharmaceutically acceptable esters of compounds offormula (VII).
 20. The compound according to claim 19, wherein Z is S.21. The compound according to claim 20, wherein Y is C—CH₃.
 22. Thecompound according to claim 21, wherein the compound of formula (VII) is2-(Ethyl-{4-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-butyl}-amino)-ethanol.23. The compound according to claim 19, wherein Z is S(O₂).
 24. Apharmaceutical composition comprising a compound according to claim 19and at least one of a pharmaceutically acceptable carrier and adjuvant.